Author: "Dominique Langin" / Publisher: hal ccsd - Searchworks@Jio Institute Digital Library Search Results

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1. The multifunctional protein E4F1 links P53 to lipid metabolism in adipocytes

Author: Matthieu, Lacroix, Laetitia K, Linares, Natalia, Rueda-Rincon, Katarzyna, Bloch, Michela, Di Michele, Carlo, De Blasio, Caroline, Fau, Laurie, Gayte, Emilie, Blanchet, Aline, Mairal, Rita, Derua, Fernando, Cardona, Diane, Beuzelin, Jean-Sebastien, Annicotte, Nelly, Pirot, Adeline, Torro, Francisco J, Tinahones, Florence, Bernex, Justine, Bertrand-Michel, Dominique, Langin, Lluis, Fajas, Johannes V, Swinnen, Laurent, Le Cam, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidad de Málaga [Málaga] = University of Málaga [Málaga], Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), CIBER of Physiopathology, Obesity and Nutrition [Malaga] (CIBEROBN), Instituto de Investigación Biomédica [Malaga, Spain] (IBIMA), Université de Lausanne = University of Lausanne (UNIL), Lacroix, Matthieu, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and University of Málaga
Subjects: Adult, Male, p53, obesity, Ubiquitin-Protein Ligases, Science, Article, Body Mass Index, Fatty Acids, Monounsaturated, ACTIVATION, Mice, CELL-CYCLE ARREST, P120(E4F), LIPOGENESIS, REVEALS, lipid metabolism, Adipocytes, Animals, Humans, Aged, Mice, Knockout, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Science & Technology, IDENTIFICATION, TRANSCRIPTION FACTOR E4F1, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, adipose tissue, Repressor Proteins, Multidisciplinary Sciences, E4F1, DIFFERENTIATION, Gene Expression Regulation, Science & Technology - Other Topics, GROWTH, Female, Insulin Resistance, Tumor Suppressor Protein p53, Fat metabolism, REGULATOR, Transcription, Stearoyl-CoA Desaturase, Signal Transduction
Abstract: Growing evidence supports the importance of the p53 tumor suppressor in metabolism but the mechanisms underlying p53-mediated control of metabolism remain poorly understood. Here, we identify the multifunctional E4F1 protein as a key regulator of p53 metabolic functions in adipocytes. While E4F1 expression is upregulated during obesity, E4f1 inactivation in mouse adipose tissue results in a lean phenotype associated with insulin resistance and protection against induced obesity. Adipocytes lacking E4F1 activate a p53-dependent transcriptional program involved in lipid metabolism. The direct interaction between E4F1 and p53 and their co-recruitment to the Steaoryl-CoA Desaturase-1 locus play an important role to regulate monounsaturated fatty acids synthesis in adipocytes. Consistent with the role of this E4F1-p53-Steaoryl-CoA Desaturase-1 axis in adipocytes, p53 inactivation or diet complementation with oleate partly restore adiposity and improve insulin sensitivity in E4F1-deficient mice. Altogether, our findings identify a crosstalk between E4F1 and p53 in the control of lipid metabolism in adipocytes that is relevant to obesity and insulin resistance., The p53 tumor suppressor is also a regulator of metabolism, but the mechanisms controlling p53-associated metabolic activities remain poorly understood. Here the authors report that the deletion of the multifunctional protein E4F1 is protective against diet-induced obesity in mice, and E4F1 regulates adipocyte lipid metabolism through p53.
Published: 2021

2. Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics

Author: Dominique Langin, Jeremie Boucher, Pauline Morigny, Peter Arner, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Helmholtz Zentrum München = German Research Center for Environmental Health, Heidelberg University Hospital [Heidelberg], German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), AstraZeneca, University of Gothenburg (GU), Karolinska Institutet [Stockholm], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Franco-czech Laboratory for clinical research on obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mégard, Roxane, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Helmholtz-Zentrum München (HZM), and CHU Toulouse [Toulouse]
Subjects: 0301 basic medicine, Anabolism, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Adipocytes, White, Adipose tissue, 030209 endocrinology & metabolism, White adipose tissue, Carbohydrate metabolism, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin resistance, medicine, Animals, Homeostasis, Humans, Obesity, Glucose metabolism, Catabolism, business.industry, Disease Management, Lipid metabolism, medicine.disease, White adipocytes, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, Adipocyte hypertrophy, business
Abstract: International audience; In mammals, the white adipocyte is a cell type that is specialized for storage of energy (in the form of triacylglycerols) and for energy mobilization (as fatty acids). White adipocyte metabolism confers an essential role to adipose tissue in whole-body homeostasis. Dysfunction in white adipocyte metabolism is a cardinal event in the development of insulin resistance and associated disorders. This Review focuses on our current understanding of lipid and glucose metabolic pathways in the white adipocyte. We survey recent advances in humans on the importance of adipocyte hypertrophy and on the in vivo turnover of adipocytes and stored lipids. At the molecular level, the identification of novel regulators and of the interplay between metabolic pathways explains the fine-tuning between the anabolic and catabolic fates of fatty acids and glucose in different physiological states. We also examine the metabolic alterations involved in the genesis of obesity-associated metabolic disorders, lipodystrophic states, cancers and cancer-associated cachexia. New challenges include defining the heterogeneity of white adipocytes in different anatomical locations throughout the lifespan and investigating the importance of rhythmic processes. Targeting white fat metabolism offers opportunities for improved patient stratification and a wide, yet unexploited, range of therapeutic opportunities.
Published: 2021

3. Reappraisal of the optimal fasting time for insulin tolerance tests in mice

Author: Claire Laurens, Marine Coué, Deborah Carper, Cedric Moro, Dominique Langin, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and CCSD, Accord Elsevier
Subjects: 0301 basic medicine, Blood Glucose, Male, medicine.medical_specialty, lcsh:Internal medicine, Weight loss, [SDV]Life Sciences [q-bio], Male mice, 030209 endocrinology & metabolism, Brief Communication, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Internal medicine, Glucose homeostasis, Medicine, Animals, Insulin, lcsh:RC31-1245, Muscle, Skeletal, Molecular Biology, 2. Zero hunger, Glycogen, business.industry, Catabolism, Body Weight, Skeletal muscle, Cell Biology, Fasting, Insulin tolerance, Glucose Tolerance Test, Muscle atrophy, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Catabolic genes, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Glucose, chemistry, Liver, medicine.symptom, Insulin Resistance, business
Abstract: Objective Most studies routinely use overnight or 6 h of fasting before testing metabolic glucose homeostasis in mice. Other studies used empirically shorter fasting times (5%) and significant changes in catabolic gene expression in the liver and skeletal muscle. Conclusion Collectively, these data suggest that 2 h of fasting appears optimal for the assessment of insulin tolerance in mice as this duration minimizes major metabolic stress and weight loss., Highlights • Fasting in mice induces time-dependent metabolic stress and weight loss. • Fasting promotes profound changes in catabolic gene expression in liver and muscles. • Fasting-induced weight loss is attenuated at thermoneutrality. • Two hours fasting appears to be optimal prior to assessing insulin tolerance in mice.
Published: 2020

4. Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans

Author: Julie Vion, Dominique Larrouy, Virginie Bourlier, Stéphane Blanc, I. Harant, Claire Laurens, Sylvie Caspar-Bauguil, Coralie Fontaine, Dominique Langin, Claire Thalamas, Pauline Maes, Marie Adeline Marques, Nathalie Viguerie, Isabelle de Glisezinski, Deborah Carper, Benjamin Lair, Emilie Montastier, Cedric Moro, Jean Louis Grolleau, Donal J. O’Gorman, Enda Murphy, Geneviève Tavernier, Fabrice Bertile, Anne Bouloumié, Nathalie Boulet, Anisha Parmar, Gaillard, Brigitte, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Ecologie, Physiologie et Ethologie (DEPE-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Centre d'investigation clinique de Toulouse (CIC 1436), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Dublin City University [Dublin] (DCU), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Dublin City University (DCU), Ireland's university of Enterprise, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Adult, Male, [SDE] Environmental Sciences, medicine.medical_specialty, Growth Differentiation Factor 15, Lipolysis, Adipose tissue, Stimulation, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Myokine, medicine, Humans, Muscle, Skeletal, Exercise, Muscle biopsy, medicine.diagnostic_test, Myogenesis, Chemistry, Skeletal muscle, General Medicine, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDE]Environmental Sciences, GDF15, Research Article
Abstract: International audience; We hypothesized that skeletal muscle contraction produces a cellular stress signal, triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying exercise-regulated myokines, also known as exerkines, able to promote lipolysis. Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. CM and human plasma samples were analyzed using unbiased proteomic screening and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples. CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes. Growth and differentiation factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was upregulated in CM from both acute and chronic exercise–stimulated myotubes. We further showed that physiological concentrations of recombinant GDF15 protein increased lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogated EPS CM-mediated lipolysis. We herein provide the first evidence to our knowledge that GDF15 is a potentially novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.
Published: 2020

5. Caloric Restriction and Diet-Induced Weight Loss Do Not Induce Browning of Human Subcutaneous White Adipose Tissue in Women and Men with Obesity

Author: Valentin Barquissau, Frédéric Martins, Ez-Zoubir Amri, Cedric Moro, Jean-José Maoret, Sébastien Déjean, Nathalie Viguerie, Arne Astrup, Didier F. Pisani, Diane Beuzelin, Jason S. Iacovoni, Dominique Langin, Wim H. M. Saris, Benjamin Léger, Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Plateforme GeT (Génome et Transcriptome), Génopole Toulouse, Institut National de la Recherche Agronomique (INRA), Institute of Developmental Biology and Cancer (IBDC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Valrose (IBV), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, NUTRIM, Department of Nutrition, Exercise and Sports [Copenhagen], Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Mathématiques de Toulouse UMR5219 (IMT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service de Pharmacologie Clinique, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie clinique, CHU Toulouse [Toulouse], Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Génome et Transcriptome - Plateforme Génomique (GeT-PlaGe), Institut National de la Recherche Agronomique (INRA)-Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Service Pharmacologie Clinique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, Humane Biologie, Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Adipose tissue, PROTEIN, White adipose tissue, BEIGE ADIPOCYTES, MOUSE, Mice, 0302 clinical medicine, FUNCTIONAL-CHARACTERIZATION, Weight loss, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], insulin resistance, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, browning of white fat, Thermogenin, Very low calorie diet, RESTING ENERGY-EXPENDITURE, VISCERAL FAT, subcutaneous abdominal white adipose tissue, caloric restriction, medicine.symptom, medicine.medical_specialty, Diet, Reducing, Adipose Tissue, White, uncoupling protein 1, sex difference, food.diet, Subcutaneous Fat, 030209 endocrinology & metabolism, DISTINCT, METABOLISM, ADULT HUMANS, General Biochemistry, Genetics and Molecular Biology, human obesity, 03 medical and health sciences, food, Insulin resistance, dietary intervention, Internal medicine, Weight Loss, medicine, Animals, Humans, Resting energy expenditure, Obesity, business.industry, medicine.disease, 030104 developmental biology, Endocrinology, lcsh:Biology (General), CELLS, business
Abstract: Summary Caloric restriction (CR) is standard lifestyle therapy in obesity management. CR-induced weight loss improves the metabolic profile of individuals with obesity. In mice, occurrence of beige fat cells in white fat depots favors a metabolically healthy phenotype, and CR promotes browning of white adipose tissue (WAT). Here, human subcutaneous abdominal WAT samples were analyzed in 289 individuals with obesity following a two-phase dietary intervention consisting of an 8 week very low calorie diet and a 6-month weight-maintenance phase. Before the intervention, we show sex differences and seasonal variation, with higher expression of brown and beige markers in women with obesity and during winter, respectively. The very low calorie diet resulted in decreased browning of subcutaneous abdominal WAT. During the whole dietary intervention, evolution of body fat and insulin resistance was independent of changes in brown and beige fat markers. These data suggest that diet-induced effects on body fat and insulin resistance are independent of subcutaneous abdominal WAT browning in people with obesity.
Published: 2018

6. Let-7i-5p represses brite adipocyte function in mice and humans

Author: Guillaume E. Beranger, Kirsi A. Virtanen, Marcel Scheideler, Maude Giroud, Pirjo Nuutila, Michael Karbiener, Dominique Langin, Tarja Niemi, Rayane A. Ghandour, Didier F. Pisani, Ez-Zoubir Amri, Markku Taittonen, Laboratoire de PhysioMédecine Moléculaire (LP2M), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Adipose Tissue, White, [SDV]Life Sciences [q-bio], Down-Regulation, White adipose tissue, Biology, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Oxygen Consumption, Downregulation and upregulation, Adipose Tissue, Brown, Internal medicine, microRNA, Brown adipose tissue, medicine, Animals, Humans, Adipocytes, Beige, Obesity, Uncoupling Protein 1, ComputingMilieux_MISCELLANEOUS, Multidisciplinary, Adipogenesis, ta3141, Thermogenesis, ta3121, Thermogenin, Gene expression profiling, Mice, Inbred C57BL, MicroRNAs, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Adipocytes, Brown, 030220 oncology & carcinogenesis, Receptors, Adrenergic, beta-3
Abstract: In response to cold or β3-adrenoreceptor stimulation brown adipose tissue (BAT) promotes non-shivering thermogenesis, leading to energy dissipation. BAT has long been thought to be absent or scarce in adult humans. The recent discovery of thermogenic brite/beige adipocytes has opened the way to development of novel innovative strategies to combat overweight/obesity and associated diseases. Thus it is of great interest to identify regulatory factors that govern the brite adipogenic program. Here, we carried out global microRNA (miRNA) expression profiling on human adipocytes to identify miRNAs that are regulated upon the conversion from white to brite adipocytes. Among the miRNAs that were differentially expressed, we found that Let-7i-5p was down regulated in brite adipocytes. A detailed analysis of the Let-7i-5p levels showed an inverse expression of UCP1 in murine and human brite adipocytes both in vivo and in vitro. Functional studies with Let-7i-5p mimic in human brite adipocytes in vitro revealed a decrease in the expression of UCP1 and in the oxygen consumption rate. Moreover, the Let-7i-5p mimic when injected into murine sub-cutaneous white adipose tissue inhibited partially β3-adrenergic activation of the browning process. These results suggest that the miRNAs Let-7i-5p participates in the recruitment and the function of brite adipocytes.
Published: 2016

7. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD

Author: Thierry Pineau, Talal Al Saati, Frédéric Lasserre, Edwin Fouché, Justine Bertrand-Michel, Laila Mselli-Lakhal, Alexandra Montagner, Dominique Langin, Fadila Benhamed, Hervé Guillou, Sandrine Lagarrigue, Simon Ducheix, Catherine Postic, Nicolas Loiseau, Céline Lukowicz, Valentin Barquissau, Patricia Cano, Gilles Mithieux, Alison Iroz, Walter Wahli, Marion Régnier, Yannick Lippi, Fabienne Rajas, Arnaud Polizzi, ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Prévention et promotion de la cancérogénèse par les aliments (ToxAlim-PPCA), Transcriptomic impact of Xenobiotics (E23 TRiX), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), U855, Nutrition et cerveau, Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage [Rennes] (PEGASE), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Nanyang Technological University [Singapour], Université de Lausanne (UNIL), Di Carlo, Marie-Ange, Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Université de Lausanne = University of Lausanne (UNIL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UPS), Université Fédérale Toulouse Midi-Pyrénées, UMR 1048 Institute of Metabolic and Cardiovascular Diseases, UMR 1048, Université Paris Descartes - Paris 5 (UPD5), Université Toulouse III - Paul Sabatier (UPS), US006/CREFRE, Centre Hospitalier Universitaire de Purpan (CHU Purpan), U855, Université de Lyon, Université de Brest (UBO), Laboratory of Clinical Biochemistry, Centre Hospitalier Universitaire de Toulouse, Lee Kong Chian School of Medicine, Center for Integrative Genomics, Université de Lausanne, ToxAlim ( ToxAlim ), Institut National Polytechnique [Toulouse] ( INP ) -Institut National de la Recherche Agronomique ( INRA ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse ( ENVT ), Institut National Polytechnique de Toulouse ( INPT ) -Institut National Polytechnique de Toulouse ( INPT ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Toulouse III - Paul Sabatier ( UPS ), Centre Hospitalier Universitaire de Purpan ( CHU Purpan ), Université de Lyon (COMUE), Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage [Rennes] ( PEGASE ), Institut National de la Recherche Agronomique ( INRA ) -AGROCAMPUS OUEST, and Université de Brest ( UBO )
Subjects: Male, 0301 basic medicine, Aging, FGF21, [ SDV.TOX ] Life Sciences [q-bio]/Toxicology, Peroxisome proliferator-activated receptor, Hypothermia, métabolisme des lipides, [ SDV.BA ] Life Sciences [q-bio]/Animal biology, Toxicology, chemistry.chemical_compound, 0302 clinical medicine, Cytochrome P-450 Enzyme System, Fenofibrate, glyceride metabolism, liver steatosis, liver function tests, Non-alcoholic Fatty Liver Disease, Adipocyte, Adipocytes, Homeostasis, Fatty acid homeostasis, Hypolipidemic Agents, Mice, Knockout, Animal biology, LIPID METABOLISM, chemistry.chemical_classification, glyceride metabolism, NONALCOHOLIC STEATOHEPATITIS, [SDV.BA]Life Sciences [q-bio]/Animal biology, Fatty Acids, Fatty liver, Gastroenterology, Fasting, foie, Liver, [SDV.TOX]Life Sciences [q-bio]/Toxicology, 030220 oncology & carcinogenesis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], expression des gènes, GENE EXPRESSION, medicine.medical_specialty, Lipolysis, Biology, liver steatosis, 03 medical and health sciences, métabolisme des lipides, expression des gènes, stéatose hépatique, foie, stéatose hépatique, Internal medicine, Biologie animale, medicine, Animals, Humans, PPAR alpha, Cytochrome P450 Family 4, RNA, Messenger, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Triglycerides, Toxicologie, Hepatology, Gene Expression Profiling, Lipid metabolism, Overweight, medicine.disease, Hypoglycemia, Mice, Inbred C57BL, Fibroblast Growth Factors, Disease Models, Animal, 030104 developmental biology, Endocrinology, chemistry, Hepatocytes, MESH: GENE EXPRESSION, liver function tests, Steatosis
Abstract: Supplementary Data : http://gut.bmj.com/content/early/2016/01/31/gutjnl-2015-310798/suppl/DC1; International audience; OBJECTIVE:Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor expressed in tissues with high oxidative activity that plays a central role in metabolism. In this work, we investigated the effect of hepatocyte PPARα on non-alcoholic fatty liver disease (NAFLD).DESIGN:We constructed a novel hepatocyte-specific PPARα knockout (Pparα(hep-/-)) mouse model. Using this novel model, we performed transcriptomic analysis following fenofibrate treatment. Next, we investigated which physiological challenges impact on PPARα. Moreover, we measured the contribution of hepatocytic PPARα activity to whole-body metabolism and fibroblast growth factor 21 production during fasting. Finally, we determined the influence of hepatocyte-specific PPARα deficiency in different models of steatosis and during ageing.RESULTS:Hepatocyte PPARα deletion impaired fatty acid catabolism, resulting in hepatic lipid accumulation during fasting and in two preclinical models of steatosis. Fasting mice showed acute PPARα-dependent hepatocyte activity during early night, with correspondingly increased circulating free fatty acids, which could be further stimulated by adipocyte lipolysis. Fasting led to mild hypoglycaemia and hypothermia in Pparα(hep-/-) mice when compared with Pparα(-/-) mice implying a role of PPARα activity in non-hepatic tissues. In agreement with this observation, Pparα(-/-) mice became overweight during ageing while Pparα(hep-/-) remained lean. However, like Pparα(-/-) mice, Pparα(hep-/-) fed a standard diet developed hepatic steatosis in ageing.CONCLUSIONS:Altogether, these findings underscore the potential of hepatocyte PPARα as a drug target for NAFLD.
Published: 2016

8. White-to-brite conversion in human adipocytes promotes metabolic reprogramming towards fatty acid anabolic and catabolic pathways

Author: Marie-Adeline Marques, Didier F. Pisani, Geneviève Tavernier, Balbine Roussel, Hervé Guillou, Cedric Moro, Aline Mairal, Dominique Langin, Ez-Zoubir Amri, Valentin Barquissau, Guillaume E. Beranger, Alexandra Montagner, Diane Beuzelin, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), RUIZ, Caroline, Université Nice Sophia Antipolis (1965 - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), and Langin, Dominique
Subjects: 0301 basic medicine, medicine.medical_specialty, lcsh:Internal medicine, Anabolism, [SDV]Life Sciences [q-bio], Brite/beige adipocyte, Peroxisome proliferator-activated receptor, Fatty acid metabolism, Glycerol metabolism, Pyruvate dehydrogenase kinase 4, Adipose tissue, 030209 endocrinology & metabolism, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Insulin resistance, Internal medicine, medicine, lcsh:RC31-1245, Molecular Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, chemistry.chemical_classification, Catabolism, Fatty acid, Cell Biology, Metabolism, medicine.disease, [SDV] Life Sciences [q-bio], 030104 developmental biology, Endocrinology, chemistry, Original Article
Abstract: Objective Fat depots with thermogenic activity have been identified in humans. In mice, the appearance of thermogenic adipocytes within white adipose depots (so-called brown-in-white i.e., brite or beige adipocytes) protects from obesity and insulin resistance. Brite adipocytes may originate from direct conversion of white adipocytes. The purpose of this work was to characterize the metabolism of human brite adipocytes. Methods Human multipotent adipose-derived stem cells were differentiated into white adipocytes and then treated with peroxisome proliferator-activated receptor (PPAR)γ or PPARα agonists between day 14 and day 18. Gene expression profiling was determined using DNA microarrays and RT-qPCR. Variations of mRNA levels were confirmed in differentiated human preadipocytes from primary cultures. Fatty acid and glucose metabolism was investigated using radiolabelled tracers, Western blot analyses and assessment of oxygen consumption. Pyruvate dehydrogenase kinase 4 (PDK4) knockdown was achieved using siRNA. In vivo, wild type and PPARα-null mice were treated with a β3-adrenergic receptor agonist (CL316,243) to induce appearance of brite adipocytes in white fat depot. Determination of mRNA and protein levels was performed on inguinal white adipose tissue. Results PPAR agonists promote a conversion of white adipocytes into cells displaying a brite molecular pattern. This conversion is associated with transcriptional changes leading to major metabolic adaptations. Fatty acid anabolism i.e., fatty acid esterification into triglycerides, and catabolism i.e., lipolysis and fatty acid oxidation, are increased. Glucose utilization is redirected from oxidation towards glycerol-3-phophate production for triglyceride synthesis. This metabolic shift is dependent on the activation of PDK4 through inactivation of the pyruvate dehydrogenase complex. In vivo, PDK4 expression is markedly induced in wild-type mice in response to CL316,243, while this increase is blunted in PPARα-null mice displaying an impaired britening response. Conclusions Conversion of human white fat cells into brite adipocytes results in a major metabolic reprogramming inducing fatty acid anabolic and catabolic pathways. PDK4 redirects glucose from oxidation towards triglyceride synthesis and favors the use of fatty acids as energy source for uncoupling mitochondria., Graphical abstract, Highlights • PPARγ and α agonists induce conversion of human white into brite adipocytes. • Fatty acid anabolism and catabolism are activated in human brite adipocytes. • Glucose use in brite adipocytes is redirected from oxidation to glyceroneogenesis. • PDK4 induction is responsible for the shift from glucose to fatty acid oxidation.
Published: 2016

9. Control of adipogenesis by oxylipins, GPCRs and PPARs

Author: Gérard Ailhaud, Rayane A. Ghandour, Ez-Zoubir Amri, Valentin Barquissau, Didier F. Pisani, Dominique Langin, Martin Klingenspor, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Service de biochimie clinique, CHU Toulouse [Toulouse], Pisani, Didier, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: 0301 basic medicine, PPARγ, Peroxisome Proliferator-Activated Receptors, Adipose tissue, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, adipocyte, Biochemistry, PPARα, Receptors, G-Protein-Coupled, 03 medical and health sciences, chemistry.chemical_compound, Lipoxygenase, 0302 clinical medicine, PPARβ/δ, Adipocyte, Animals, Humans, Oxylipins, prostanoid, Receptor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, G protein-coupled receptor, Adipogenesis, General Medicine, Peroxisome, Eicosanoid, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, 030104 developmental biology, chemistry, Nuclear receptor, biology.protein, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery
Abstract: International audience; Oxylipins are bioactive metabolites derived from the oxygenation of ω3 and ω6 polyunsaturated fatty acids, triggered essentially by cyclooxygenase and lipoxygenase activities. Oxylipins are involved in the development and function of adipose tissue and their productions are strictly related to diet quality and quantity. Oxylipins signal via cell surface membrane (G Protein-coupled receptors) and nuclear receptors (peroxisome proliferator-activated receptors), two pathways playing a pivotal role in adipocyte biology. In this review, we made an attempt to cover the available knowledge about synthesis and molecular function of oxylipins known to modulate adipogenesis, adipocyte function and phenotype conversion, with a focus on their interaction with peroxisome proliferator-activated nuclear receptor family.
Published: 2016

10. Positive interaction between prebiotics and thiazolidinedione treatment on adiposity in diet-induced obese mice

Author: Maud, Alligier, Evelyne M, Dewulf, Nuria, Salazar, Aline, Mairal, Audrey M, Neyrinck, Patrice D, Cani, Dominique, Langin, Nathalie M, Delzenne, Nutrition and Metabolism Research Group (LDRI), Université Catholique de Louvain = Catholic University of Louvain (UCL), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Walloon Excellence in Life sciences and BIOtechnology [Liège] (WELBIO), Service de biochimie clinique, CHU Toulouse [Toulouse], Simon, Marie Francoise, Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Blood Glucose, Male, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Pioglitazone, Subcutaneous Fat, Mice, Obese, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Diet, High-Fat, Mice, Inbred C57BL, PPAR gamma, Mice, Prebiotics, Adipocytes, Animals, Homeostasis, Insulin, Thiazolidinediones, Adiponectin, Adiposity
Abstract: International audience; OBJECTIVES: To investigate whether inulin-type fructan (ITF) prebiotics could counteract the thiazolidinedione (TZD, PPARγ activator) induced-fat mass gain, without affecting its beneficial effect on glucose homeostasis, in high-fat (HF) diet fed mice. METHODS: Male C57bl6/J mice were fed a HF diet alone or supplemented with ITF prebiotics (0.2 g/day × mouse) or TZD (30 mg pioglitazone (PIO)/kg body weight × day) or both during 4 weeks. An insulin tolerance test was performed after 3 weeks of treatment. RESULTS: As expected, PIO improved glucose homeostasis and increased adiponectinaemia. Furthermore, it induced an over-expression of several PPARγ target genes in white adipose tissues. ITF prebiotics modulated the PIO-induced PPARγ activation in a tissue-dependent manner. The co-treatment with ITF prebiotics and PIO maintained the beneficial impact of TZD on glucose homeostasis and adiponectinaemia. Moreover, the combination of both treatments reduced fat mass accumulation, circulating lipids and hepatic triglyceride content, suggesting an overall improvement of metabolism. Finally, the co-treatment favored induction of white-to-brown fat conversion in subcutaneous adipose tissue, thereby leading to the development of brite adipocytes that could increase the oxidative capacity of the tissue. CONCLUSIONS: ITF prebiotics decrease adiposity and improve the metabolic response in HF fed mice treated with TZD.
Published: 2014

11. Lipolysis in lipid turnover, cancer cachexia, and obesity-induced insulin resistance

Author: Peter Arner, Dominique Langin, Department of Medicine at Karolinska University Hospital, Karolinska Institutet [Stockholm], Service de biochimie clinique, CHU Toulouse [Toulouse], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: medicine.medical_specialty, Cachexia, Endocrinology, Diabetes and Metabolism, Lipolysis, Adipose tissue, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Paracrine signalling, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Insulin resistance, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell surface receptor, Lipid droplet, Internal medicine, Neoplasms, medicine, Humans, Obesity, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Triglyceride, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Lipid Metabolism, 3. Good health, chemistry, 030220 oncology & carcinogenesis, Insulin Resistance, Hormone
Abstract: International audience; Triglycerides in adipose tissue are rapidly mobilized during times of energy needs via lipolysis, a catabolic process that plays important role in whole body triglyceride turnover. Lipolysis is regulated through cell surface receptors via neurotransmitters, hormones, and paracrine factors that activate various intracellular pathways. These pathways converge on the lipid droplet, the site of action of lipases and cofactors. Fat cell lipolysis is also involved in the pathogenesis of metabolic disorders, and recent human studies have underscored its role in disease states such as cancer cachexia and obesity-induced insulin resistance. We highlight here topics and findings with physiological and clinical relevance, namely lipid turnover in human fat cells and the role of lipolysis in cancer cachexia and obesity-induced insulin resistance.
Published: 2014

12. Semaphorin 3C is a novel adipokine linked to extracellular matrix composition

Author: Vanessa Pellegrinelli, Joan Tordjman, Erik Näslund, Anne Bouloumié, Niklas Mejhert, P. Lång, Vladimir Stich, Nathalie Viguerie, Catherine-Ines Kolditz, Dominique Langin, Jean Galitzky, Ingrid Dahlman, D Lacasa, Mikael Rydén, Paul Trayhurn, Karine Clément, Daniel Esteve, Florian Wilfling, Department of Medicine, Lipid Laboratory (NOVUM), Karolinska Institutet [Stockholm], Department of Cell Biology [New Haven], Yale University School of Medicine-Howard Hughes Medical Institute (HHMI), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Division of Surgery, Department of Clinical Sciences, Karolinska Institutet [Stockholm]-Danderyd Hospital, Obesity Biology Unit, University of Liverpool, Clore Laboratory, University of Buckingham, Department of Sports Medicine, Charles University [Prague] (CU), Department of Laboratory Medicine, Laboratoire de Biochimie [Purpan IFB], CHU Toulouse [Toulouse], Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Simon, Marie Francoise, Yale School of Medicine [New Haven, Connecticut] (YSM)-Howard Hughes Medical Institute (HHMI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Karolinska Institutet [Stockholm]-Danderyds sjukhus = Danderyd University Hospital, Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Department of Medicine, Lipid Laboratory ( NOVUM ), Yale School of Medicine-Howard Hugues Medical Institute, Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Cardiométabolisme et Nutrition, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Charles University [Prague], Université Toulouse III - Paul Sabatier ( UPS ), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, Adipose Tissue, White, Endocrinology, Diabetes and Metabolism, Fluorescent Antibody Technique, Adipose tissue, Adipokine, Enzyme-Linked Immunosorbent Assay, 030209 endocrinology & metabolism, Semaphorins, White adipose tissue, Biology, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, Adipokines, Semaphorin, Fibrosis, Internal medicine, Internal Medicine, medicine, Humans, Secretion, Cells, Cultured, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Microscopy, Confocal, food and beverages, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Immunohistochemistry, Extracellular Matrix, Endocrinology, Function (biology)
Abstract: International audience; AIMS/HYPOTHESIS: Alterations in white adipose tissue (WAT) function, including changes in protein (adipokine) secretion and extracellular matrix (ECM) composition, promote an insulin-resistant state. We set out to identify novel adipokines regulated by body fat mass in human subcutaneous WAT with potential roles in adipose function. METHODS: Adipose transcriptome data and secretome profiles from conditions with increased/decreased WAT mass were combined. WAT donors were predominantly women. In vitro effects were assessed using recombinant protein. Results were confirmed by quantitative PCR/ELISA, metabolic assays and immunochemistry in human WAT and adipocytes. RESULTS: We identified a hitherto uncharacterised adipokine, semaphorin 3C (SEMA3C), the expression of which correlated significantly with body weight, insulin resistance (HOMA of insulin resistance [HOMAIR], and the rate constant for the insulin tolerance test [KITT]) and adipose tissue morphology (hypertrophy vs hyperplasia). SEMA3C was primarily found in mature adipocytes and had no direct effect on human adipocyte differentiation, lipolysis, glucose transport or the expression of β-oxidation genes. This could in part be explained by the significant downregulation of its cognate receptors during adipogenesis. In contrast, in pre-adipocytes, SEMA3C increased the production/secretion of several ECM components (fibronectin, elastin and collagen I) and matricellular factors (connective tissue growth factor, IL6 and transforming growth factor-β1). Furthermore, the expression of SEMA3C in human WAT correlated positively with the degree of fibrosis in WAT. CONCLUSIONS/INTERPRETATION: SEMA3C is a novel adipokine regulated by weight changes. The correlation with WAT hypertrophy and fibrosis in vivo, as well as its effects on ECM production in human pre-adipocytes in vitro, together suggest that SEMA3C constitutes an adipocyte-derived paracrine signal that influences ECM composition and may play a pathophysiological role in human WAT.
Published: 2013

13. High-fat diet-mediated lipotoxicity and insulin resistance is related to impaired lipase expression in mouse skeletal muscle

Author: Pierre Marie Badin, Aline Mairal, Marie Adeline Marques, Virginie Bourlier, Isabelle K. Vila, Cedric Moro, Katie Louche, Dominique Langin, Geneviève Tavernier, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de biochimie clinique, CHU Toulouse [Toulouse], Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Simon, Marie Francoise
Subjects: medicine.medical_treatment, Glucose uptake, Muscle Proteins, Weight Gain, MESH: Mice, Knockout, MESH: Lipase, Mice, 0302 clinical medicine, Endocrinology, Insulin, MESH: Animals, Phosphorylation, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Mice, Knockout, 0303 health sciences, Mice, Inbred C3H, MESH: Muscle, Skeletal, biology, Intracellular Signaling Peptides and Proteins, food and beverages, 1-Acylglycerol-3-Phosphate O-Acyltransferase, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, MESH: Glucose, MESH: Insulin Resistance, medicine.anatomical_structure, Lipotoxicity, MESH: Weight Gain, MESH: Membrane Proteins, medicine.medical_specialty, MESH: 1-Acylglycerol-3-Phosphate O-Acyltransferase, MESH: Glucose Tolerance Test, 030209 endocrinology & metabolism, MESH: Carrier Proteins, MESH: Insulin, Diet, High-Fat, Perilipin-2, Perilipin-3, Diglycerides, MESH: Diglycerides, 03 medical and health sciences, MESH: Muscle Proteins, Insulin resistance, Internal medicine, MESH: Intracellular Signaling Peptides and Proteins, medicine, Animals, Muscle, Skeletal, MESH: Mice, Inbred C3H, MESH: Mice, 030304 developmental biology, MESH: Phosphorylation, Skeletal muscle, Membrane Proteins, Lipase, Glucose Tolerance Test, medicine.disease, IRS1, Insulin receptor, MESH: Diet, High-Fat, Glucose, Adipose triglyceride lipase, biology.protein, Insulin Resistance, Carrier Proteins
Abstract: Elevated expression/activity of adipose triglyceride lipase (ATGL) and/or reduced activity of hormone-sensitive lipase (HSL) in skeletal muscle are causally linked to insulin resistance in vitro. We investigated here the effect of high-fat feeding on skeletal muscle lipolytic proteins, lipotoxicity, and insulin signaling in vivo. Five-week-old C3H mice were fed normal chow diet (NCD) or 45% kcal high-fat diet (HFD) for 4 weeks. Wild-type and HSL knockout mice fed NCD were also studied. Whole-body and muscle insulin sensitivity, as well as lipolytic protein expression, lipid levels, and insulin signaling in skeletal muscle, were measured. HFD induced whole-body insulin resistance and glucose intolerance and reduced skeletal muscle glucose uptake compared with NCD. HFD increased skeletal muscle total diacylglycerol (DAG) content, protein kinase Cθ and protein kinase Cϵ membrane translocation, and impaired insulin signaling as reflected by a robust increase of basal Ser1101 insulin receptor substrate 1 phosphorylation (2.8-fold, P < .05) and a decrease of insulin-stimulated v-Akt murine thymoma viral oncogene homolog Ser473 (−37%, P < .05) and AS160 Thr642 (−47%, P
Published: 2013

14. Change in proportional protein intake in a 10-week energy-restricted low- or high-fat diet, in relation to changes in body size and metabolic factors

Author: J. Alfredo Martínez, Jan Polak, Claus Holst, Tanja Stocks, Thorkild I. A. Sørensen, Wim H. M. Saris, Arne Astrup, Peter Arner, Stephan Rössner, Ian A. Macdonald, Jean-Michel Oppert, Lars Ängquist, Dominique Langin, Moira A. Taylor, Institute of Preventive Medicine, Copenhagen University Hospital-Bispebjerg and Frederiksberg Hospitals, Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, School of Biomedical Sciences, University of Nottingham, UK (UON), Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Centre de Recherche en Nutrition Humaine d'Ile-de-France (CRNH-IDF), Université Paris 13 (UP13)-CETAF-Institut National Agronomique Paris-Grignon (INA P-G)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut de Veille Sanitaire (INVS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), The Obesity Unit, Department of Medicine, Department of Sports Medicine, Centre of Preventive Medicine, Third Faculty of Medicine, Charles University, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Human Biology, Nutrition and Toxicology, Maastricht University [Maastricht]-Research Institute Maastricht, Department of Nutrition, Exercise and Sports [Copenhagen], Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Université Paris 13 (UP13)-CETAF-Institut National Agronomique Paris-Grignon (INA P-G)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut de Veille Sanitaire (INVS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Simon, Marie Francoise, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Health (social science), 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, Weight loss, 030212 general & internal medicine, Diet, Fat-Restricted, lcsh:RC620-627, Dietary fats, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, Nutrition and Dietetics, Dietary intake, Blood glucoses, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Protein intake, Lipids, Näringslära, lcsh:Nutritional diseases. Deficiency diseases, Cholesterol, Endokrinologi och diabetes, Original Article, Female, medicine.symptom, lcsh:Nutrition. Foods and food supply, Adult, medicine.medical_specialty, Dietary proteins, Diet, Reducing, lcsh:TX341-641, Body size, Endocrinology and Diabetes, Diet, High-Fat, 03 medical and health sciences, Physiology (medical), Internal medicine, Weight Loss, medicine, Humans, Blood glucose, Obesity, Triglycerides, Caloric Restriction, Triglyceride, business.industry, High fat diet, Feeding Behavior, medicine.disease, Endocrinology, chemistry, Energy Intake, business
Abstract: Objective: To investigate in a secondary analysis of a randomised trial the effects of a low-/high-fat diet and reported change from baseline in energy% from protein (prot%), in relation to changes in body size and metabolic factors. Methods: Obese adults (n = 771) were randomised to a 600 kcal energy-deficient low-fat (20-25 fat%) or high-fat (40-45 fat%) diet over 10 weeks. Dietary intake data at baseline and during the intervention were available in 585 completers. We used linear regression to calculate the combined effects of randomised group and groups of prot% change (2) on outcomes. Results: The low-fat group with >2 prot% increase lost 1.1 kg more weight (p = 0.03) and reduced cholesterol by 0.25 mmol/l more (p = 0.003) than the high-fat group with >2 prot% decrease. These differences were 2.5-fold and 1.8-fold greater than the differences between the low-fat and high-fat groups while not considering prot% change. The high-fat group reduced plasma triglycerides more than the low-fat group, but not compared to those in the low-fat group with >2 units prot% increase (p fat-protein interaction = 0.01). Conclusions: Under energy restriction, participants on a low-fat diet who had increased the percentage energy intake from protein showed the greatest reduction in weight and cholesterol, and a triglyceride reduction equally large to that of participants on a high-fat diet.
Published: 2013

15. Determinants of human adipose tissue gene expression: impact of diet, sex, metabolic status, and cis genetic regulation

Author: Balbine Roussel, Hubert Vidal, Karine Clément, Dominique Langin, Arne Astrup, Nathalie Viguerie, Jason S. Iacovoni, Claus Holst, Marion Combes, Nathalie Villa-Vialaneix, Jörg Hager, Carine Valle, J. Alfredo Martínez, Emilie Montastier, Jean-José Maoret, Wim H. M. Saris, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Statistique, Analyse et Modélisation Multidisciplinaire (SAmos-Marin Mersenne) (SAMM), Université Paris 1 Panthéon-Sorbonne (UP1), Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), Institute of Preventive Medicine, Copenhagen University Hospitals, Department of Human Nutrition, Faculty of Life Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Franco-czech Laboratory for clinical research on obesity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Charles University [Prague] (CU), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], European Communities [DiOGenes FP6-513946, MoIPAGE LSHG-CT-2004-512066, ADAPT HEALTH-F2-2008-2011 00], Fondation pour la Recherche Medicale ANR LIPOB and OBELIP, Region Midi-Pyrenees, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Vialaneix, Nathalie, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de médecine moléculaire de Rangueil ( I2MR ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Statistique, Analyse et Modélisation Multidisciplinaire (SAmos-Marin Mersenne) ( SAMM ), Université Panthéon-Sorbonne ( UP1 ), Universidad de Navarra [Pamplona] ( UNAV ), Faculty of Life Sciences-University of Copenhagen ( KU ), Cardiovasculaire, métabolisme, diabétologie et nutrition ( CarMeN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National de la Recherche Agronomique ( INRA ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Genomics Institute, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Charles University [Prague]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Panthéon-Sorbonne (UP1), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Charles University [Prague]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Cancer Research, Adipose tissue, Gene Expression, [SDV.GEN] Life Sciences [q-bio]/Genetics, Body Mass Index, 0302 clinical medicine, Weight loss, Gene expression, Molecular Cell Biology, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), 2. Zero hunger, Regulation of gene expression, Gene expression regulation, Metabolic Syndrome, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Genomics, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Santé publique et épidémiologie, obésité, Adipose Tissue, Medicine, Female, medicine.symptom, Research Article, medicine.medical_specialty, lcsh:QH426-470, Calorie restriction, Médecine humaine et pathologie, 030209 endocrinology & metabolism, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, Sex Factors, Internal medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Weight Loss, medicine, Genetics, Genome-Wide Association Studies, Humans, Obesity, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Nutrition, Caloric Restriction, Regulatory Networks, [SDV.GEN]Life Sciences [q-bio]/Genetics, Lipogenesis, Computational Biology, Human Genetics, medicine.disease, lcsh:Genetics, Endocrinology, Gene Expression Regulation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Human health and pathology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Metabolic syndrome, Genome Expression Analysis, Energy Intake, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Body mass index, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Weight control diets favorably affect parameters of the metabolic syndrome and delay the onset of diabetic complications. The adaptations occurring in adipose tissue (AT) are likely to have a profound impact on the whole body response as AT is a key target of dietary intervention. Identification of environmental and individual factors controlling AT adaptation is therefore essential. Here, expression of 271 transcripts, selected for regulation according to obesity and weight changes, was determined in 515 individuals before, after 8-week low-calorie diet-induced weight loss, and after 26-week ad libitum weight maintenance diets. For 175 genes, opposite regulation was observed during calorie restriction and weight maintenance phases, independently of variations in body weight. Metabolism and immunity genes showed inverse profiles. During the dietary intervention, network-based analyses revealed strong interconnection between expression of genes involved in de novo lipogenesis and components of the metabolic syndrome. Sex had a marked influence on AT expression of 88 transcripts, which persisted during the entire dietary intervention and after control for fat mass. In women, the influence of body mass index on expression of a subset of genes persisted during the dietary intervention. Twenty-two genes revealed a metabolic syndrome signature common to men and women. Genetic control of AT gene expression by cis signals was observed for 46 genes. Dietary intervention, sex, and cis genetic variants independently controlled AT gene expression. These analyses help understanding the relative importance of environmental and individual factors that control the expression of human AT genes and therefore may foster strategies aimed at improving AT function in metabolic diseases., Author Summary In obesity, an excess of adipose tissue is associated with dyslipidemia and diabetic complications. Gene expression is under the control of various genetic and environmental factors. As a central organ for the control of metabolic disturbances in conditions of both weight gain and loss, a comprehensive understanding of the control of adipose tissue gene expression is of paramount interest. We analyzed adipose tissue gene expression in obese individuals from the DiOGenes protocol, one of the largest dietary interventions worldwide. We found evidence for composite control of adipose tissue gene expression by nutrition, metabolic syndrome, body mass index, sex, and genotype with two main novel features. First, we observed a preeminent effect of sex on adipose tissue gene expression, which was independent of nutritional status, fat mass, and sex chromosomes. Second, the control of gene expression by cis genetic factors was unaffected by sex and nutritional status. Altogether, the effects of the investigated factors were most often independent of each other. Comprehension of the relative importance of environmental and individual factors that control the expression of human adipose tissue genes may help deciphering strategies aimed at controlling adipose tissue function during metabolic disorders.
Published: 2012

16. Adipose Tissue Secretion and Expression of Adipocyte-Produced and Stromavascular Fraction-Produced Adipokines Vary during Multiple Phases of Weight-Reducing Dietary Intervention in Obese Women

Author: Zuzana Kovacova, Jan Polak, Dominique Langin, Michaela Tencerová, Vladimir Stich, Magda Bajzova, Michaela Siklova-Vitkova, Eva Klimcakova, Lenka Rossmeislová, Department of Sports Medicine, Charles University [Prague] (CU), Franco-czech Laboratory for clinical research on obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 2nd Internal Medicine Department, Vinohrady Teaching Hospital, Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: Adult, medicine.medical_specialty, Diet, Reducing, Diet therapy, Endocrinology, Diabetes and Metabolism, food.diet, Clinical Biochemistry, Adipose tissue, Adipokine, 030209 endocrinology & metabolism, Context (language use), Cell Fractionation, Biochemistry, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, food, Insulin resistance, Adipokines, Adipocyte, Internal medicine, Adipocytes, medicine, Humans, Obesity, Caloric Restriction, 030304 developmental biology, 2. Zero hunger, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, business.industry, Biochemistry (medical), Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Very low calorie diet, Adipose Tissue, chemistry, Female, Endothelium, Vascular, Stromal Cells, business
Abstract: International audience; Context: Obesity is associated with altered plasma levels of adipokines involved in the development of insulin resistance and obesity-related metabolic disturbances. Objective: The aim was to investigate diet-induced changes in adipokine production in sc abdominal adipose tissue (SAT) during a 6-month, multiphase, weight-reducing dietary intervention. Design, Setting, Participants, and Interventions: Forty-eight obese women followed a dietary intervention consisting of a very low-calorie diet (VLCD) (1 month), followed by a weight-stabilization (WS) period, which consisted of a low-calorie diet (2 months), and a weight-maintenance diet (3 months). Main Outcome Measures: Before and at the end of the VLCD and WS, samples of plasma and SAT were obtained. In a subgroup of 26 women, secretion of adipokines was determined in SAT explants, and in a subgroup of 22 women, SAT mRNA expression was measured. Results: Body weight decreased and insulin sensitivity increased during the intervention. Plasma levels, SAT mRNA expression, and secretion rates of adipocyte-produced adipokines (leptin, serum amyloid A, and haptoglobin) decreased during the VLCD and increased during the WS period. Adipokines produced mainly from stroma-vascular cells (IL-6, IL-8, IL-10, IL-1Ra, TNFα, plasminogen activator inhibitor-1, and monocyte chemoattractant protein-1) increased or remained unchanged during VLCD and decreased to levels equal to or lower than prediet levels during the WS period. The diet-induced changes in homeostasis model assessment of insulin resistance correlated with changes in leptin plasma levels during VLCD, WS, and the entire dietary intervention period. Conclusions: Diet-induced regulation of adipokine production in SAT differs according to their cellular origin (adipocytes vs. stroma-vascular cells) and diet phase (VLCD vs. WS). Insulin-sensitivity changes were associated only with those of plasma leptin.
Published: 2012

17. Hidden variant of ChREBP in fat links lipogenesis to insulin sensitivity

Author: Renaud Dentin, Catherine Postic, Dominique Langin, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Simon, Marie Francoise, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Gene isoform, medicine.medical_specialty, Physiology, 030209 endocrinology & metabolism, White adipose tissue, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Carbohydrate-responsive element-binding protein, Molecular Biology, Transcription factor, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Mechanism (biology), Chemistry, Glucose transporter, Insulin sensitivity, Cell Biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Endocrinology, Lipogenesis
Abstract: Summary The prevalence of obesity and type 2-diabetes is increasing worldwide and threatens to shorten lifespan. Impaired insulin action in peripheral tissues is a major pathogenic factor. Insulin stimulates glucose uptake in adipose tissue through the Glut4-glucose transporter and alterations in adipose-Glut4 expression or function regulate systemic insulin sensitivity. Downregulation of adipose tissue-Glut4 occurs early in diabetes development. Here we report that adipose tissue-Glut4 regulates the expression of carbohydrate responsive-element binding protein (ChREBP), a transcriptional regulator of lipogenic and glycolytic genes. Furthermore, adipose-ChREBP is a major determinant of adipose tissue fatty acid synthesis and systemic insulin sensitivity. We discovered a new mechanism for glucose-regulation of ChREBP: Glucose-mediated activation of the canonical ChREBP isoform (ChREBPα) induces expression of a novel, potent isoform (ChREBPβ) that is transcribed from an alternative promoter. ChREBPβ expression in human adipose tissue predicts insulin sensitivity indicating that it may be an effective target for treating diabetes.
Published: 2012

18. Adipocyte lipases and lipid droplet-associated proteins: insight from transgenic mouse models

Author: Amandine Girousse, Dominique Langin, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: MESH: Triglycerides, MESH: Mice, Transgenic, Lipolysis, Endocrinology, Diabetes and Metabolism, Perilipin 2, Medicine (miscellaneous), Adipose tissue, Mice, Transgenic, 030209 endocrinology & metabolism, MESH: Carrier Proteins, [SDV.GEN] Life Sciences [q-bio]/Genetics, Fatty Acid-Binding Proteins, MESH: Fatty Acid-Binding Proteins, Perilipin-2, Perilipin-3, Mice, 03 medical and health sciences, 0302 clinical medicine, Lipid droplet, Adipocytes, Contactin 2, Animals, MESH: Animals, MESH: Lipolysis, Lipase, MESH: Mice, Triglycerides, MESH: Adipocytes, 030304 developmental biology, Diacylglycerol kinase, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Nutrition and Dietetics, MESH: Sterol Esterase, biology, Chemistry, Membrane Proteins, Sterol Esterase, Biochemistry, Adipose triglyceride lipase, biology.protein, Perilipin, MESH: Contactin 2, MESH: Membrane Proteins, Carrier Proteins
Abstract: International audience; Adipose tissue lipolysis is the catabolic process whereby stored triacylglycerol (TAG) is broken down by lipases into fatty acids and glycerol. Here, we review recent insights from transgenic mouse models. Genetic manipulations affecting lipases are considered first, followed by transgenic models of lipase co-factors and lastly non-lipase lipid droplet (LD)-associated proteins. The central role of hormone-sensitive lipase (HSL), long considered to be the sole rate-limiting enzyme of TAG hydrolysis, has been revised since the discovery of adipose triglyceride lipase (ATGL). It is now accepted that ATGL initiates TAG breakdown producing diacylglycerol, which is subsequently hydrolyzed by HSL. Furthermore, lipase activities are modulated by co-factors whose deletion causes severe metabolic disturbances. Another major advance has come from the description of the involvement of non-lipase proteins in the regulation of lipolysis. The role of perilipins has been extensively investigated. Other newly discovered LD-associated proteins have also been shown to regulate lipolysis.
Published: 2012

19. Catecholamine and insulin control of lipolysis in subcutaneous adipose tissue during long-term diet-induced weight loss in obese women

Author: Jan Polak, Isabelle de Glisezinski, Marie Adeline Marques, Katrien Koppo, Dominique Langin, Michel Berlan, Michaela Siklova-Vitkova, Vladimir Stich, Jens Bülow, Johan Van de Voorde, Eva Klimcakova, Department of Sports Medicine, Charles University [Prague] (CU), Department of Pharmacology, Universiteit Gent = Ghent University [Belgium] (UGENT), Franco-czech Laboratory for clinical research on obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Physiology, Bispebjerg Hospital-Universiy of Copenhagen, Service de biochimie clinique, CHU Toulouse [Toulouse], Service de médecine du sport, Simon, Marie Francoise, Universiteit Gent = Ghent University (UGENT), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Médecine du Sport [CHU Toulouse], Département Chirurgie Orthopédique et traumatologique [CHU Toulouse], Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Physiology, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Adipose tissue, Adrenergic, MESH: Glucose Clamp Technique, 0302 clinical medicine, Catecholamines, Weight loss, Medicine, Insulin, MESH: Obesity, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Diet, Reducing, 0303 health sciences, Glucose clamp technique, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Insulin Resistance, Epinephrine, Adipose Tissue, Female, medicine.symptom, MESH: Adipose Tissue, medicine.drug, Adult, medicine.medical_specialty, Diet, Reducing, Lipolysis, Calorie restriction, 030209 endocrinology & metabolism, MESH: Insulin, 03 medical and health sciences, MESH: Weight Loss, Physiology (medical), Internal medicine, Weight Loss, MESH: Catecholamines, Humans, MESH: Lipolysis, Obesity, 030304 developmental biology, Caloric Restriction, MESH: Caloric Restriction, MESH: Humans, business.industry, MESH: Adult, Endocrinology, Glucose Clamp Technique, Insulin Resistance, business, MESH: Female
Abstract: The aim of this study was to investigate the evolution of the adrenergic and insulin-mediated regulation of lipolysis during different phases of a 6-mo dietary intervention. Eight obese women underwent a 6-mo dietary intervention consisting of a 1-mo very low-calorie diet (VLCD) followed by a 2-mo low-calorie diet (LCD) and 3-mo weight maintenance (WM) diet. At each phase of the dietary intervention, microdialysis of subcutaneous adipose tissue (SCAT) was performed at rest and during a 3-h hyperinsulinemic euglycemic clamp. Responses of dialysate glycerol concentration (DGC) were determined at baseline and during local perfusions with adrenaline or adrenaline and phentolamine before and during the last 30 min of the clamp. Dietary intervention induced a body weight reduction and an improved insulin sensitivity. DGC progressively decreased during the clamp, and this decrease was similar during the different phases of the diet. The adrenaline-induced increase in DGC was higher at VLCD and LCD compared with baseline condition and returned to prediet levels at WM. In the probe with adrenaline and phentolamine, the increase in DGC was higher than that in the adrenaline probe at baseline and WM, but it was not different at VLCD and LCD. The results suggest that the responsiveness of SCAT to adrenaline-stimulated lipolysis increases during the calorie-restricted phases due to a reduction of the α2-adrenoceptor-mediated antilipolytic action of adrenaline. At WM, adrenaline-stimulated lipolysis returned to the prediet levels. Furthermore, no direct relationship between insulin sensitivity and the diet-induced changes in the regulation of lipolysis was found.
Published: 2012

20. Multiple effects of a short-term dexamethasone treatment in human skeletal muscle and adipose tissue

Author: Flora Picard, Carine Valle, P. Barbe, Jason S. Iacovoni, Nathalie Viguerie, Balbine Roussel, Wim H. M. Saris, Gabby B. Hul, Dominique Langin, Simon, Marie Francoise, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Department of Human Biology, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht]-Maastricht University [Maastricht], Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], and CHU Toulouse [Toulouse]
Subjects: Male, MESH: Serum Amyloid A Protein, Physiology, Adipose tissue, Dexamethasone, ACTIVATION, 0302 clinical medicine, Mineralocorticoid receptor, Longitudinal Studies, MESH: Longitudinal Studies, GENE-EXPRESSION, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, MESH: Muscle, Skeletal, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, C-Reactive Protein, medicine.anatomical_structure, Adipose Tissue, MESH: Dexamethasone, medicine.symptom, Glucocorticoid, MESH: Adipose Tissue, medicine.drug, Adult, medicine.medical_specialty, Adipose tissue macrophages, 030209 endocrinology & metabolism, Inflammation, Biology, METABOLISM, 03 medical and health sciences, Downregulation and upregulation, MICROARRAY, INFLAMMATION, Internal medicine, MESH: C-Reactive Protein, Genetics, medicine, gene expression profiling, Humans, GLUCOCORTICOIDS, Muscle, Skeletal, 030304 developmental biology, Serum Amyloid A Protein, MESH: Humans, Skeletal muscle, 3T3-L1 ADIPOCYTES, MESH: Adult, INSULIN-RESISTANT MICE, MESH: Male, Endocrinology, healthy volunteers, SERUM-AMYLOID-A, CELLS, glucocorticoid, MESH: Glucocorticoids
Abstract: Viguerie N, Picard F, Hul G, Roussel B, Barbe P, Iacovoni JS, Valle C, Langin D, Saris WHM. Multiple effects of a short-term dexamethasone treatment in human skeletal muscle and adipose tissue. Physiol Genomics 44: 141-151, 2012. First published November 22, 2011; doi:10.1152/physiolgenomics.00032.2011.-Glucocorticoids are frequently prescribed drugs with important side-effects such as glucose intolerance and tissue remodeling. The goal was to explore the molecular basis of the response of skeletal muscle and adipose tissue during a short-term dexamethasone treatment to better understand the induction of side-effects of glucocorticoids on these metabolic tissues. Fifteen healthy male subjects were assigned to a 4-day treatment with dexamethasone at 4 mg/day. The primary outcome measures were changes in gene expression profiling of subcutaneous skeletal muscle and adipose tissue. Urinary cortisol, plasma, and metabolic biochemistry were also assessed. In both tissues the prominent observation was a response to stress and increased inflammatory responses. An upregulation of the serum amyloid A was detected in skeletal muscle, adipose tissue, and plasma, whereas circulating levels of C reactive protein, another acute phase protein, decreased along with a worsened insulin sensitivity index. As tissue-specific features, tissue remodeling was shown in skeletal muscle while the adipose tissue exhibited a decreased energy metabolism. Several limitations might be raised due to the small number of subjects investigated: a possible cross talk with the mineralocorticoid receptor, and a single time point may not identify regulations occurring during longitudinal treatment. In line with the known physiological effect of glucocorticoids the early modulation of stress response genes was observed. An unexpected feature was the upregulation of the inflammatory and immune pathways. The identification of novel impact on two glucocorticoid target tissues provides a molecular basis for the design of more specific glucocorticoids devoid of adverse effects.
Published: 2012

21. Dietary Factors Impact on the Association between CTSS Variants and Obesity Related Traits

Author: Henri Hooton, Jörg Hager, Domenico Palli, Karani Santhanakrishnan Vimaleswaran, Dominique Langin, Heiner Boeing, Marianne Uhre Jakobsen, Anne Tjønneland, Claus Holst, Edith J. M. Feskens, Karine Clément, NJ Wareham, Rikke Dalgaard Hansen, Nina Roswall, Kim Overvad, Lars Ängquist, Nabila Bouatia-Naji, Wim H. M. Saris, Karina Meidtner, Giovanna Masala, Francis Rousseau, Ruth J. F. Loos, Daphne L. van der A, Thorkild I. A. Sørensen, Simon, Marie Francoise, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute of Preventive Medicine, Copenhagen University Hospitals, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), INTEGRAGEN, IntegraGen, Cancer Epidemiology Institute, Danish Cancer Society, National Institute for Public Health and the Environment [Bilthoven] (RIVM), Department of Cardiology, Aarhus University Hospital, Department of Clinical Epidemiology, Department of Epidemiology, German Institute of Human Nutrition, Molecular and Nutritional Epidemiology Unit (ISPO), Cancer Research and Prevention Institute, Epidemiology Unit, Addenbrooke's Hospital-Medical Research Council (MRC), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Human Biology (NUTRIM), Nutrition and Toxicology Research Institute of Maastricht, Division of Human Nutrition, Wageningen University and Research [Wageningen] (WUR), Centre for Paediatric Epidemiology and Biostatistics and MRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie clinique, CHU Toulouse [Toulouse], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), National Institute for Public Health and the Environment [Bilthoven] ( RIVM ), Aalborg Hospital-Aarhus University Hospital, Molecular and Nutritional Epidemiology Unit ( ISPO ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Human Biology ( NUTRIM ), Wageningen University and Research Centre [Wageningen] ( WUR ), Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), The Novo Nordisk Foundation Center for Basic Metabolic Research, Universiy of Copenhagen, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Humane Biologie, and RS: NUTRIM - R1 - Metabolic Syndrome
Subjects: Male, Nutrition and Disease, Epidemiology, lcsh:Medicine, adipose-tissue, Biochemistry, Body Mass Index, Cohort Studies, 0302 clinical medicine, Weight loss, Voeding en Ziekte, cathepsin-k gene, Body Fat Distribution, lcsh:Science, 2. Zero hunger, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Multidisciplinary, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, low-fat diets, Lipids, Glycemic index, Genetic Epidemiology, Medicine, Female, women, Dietary Proteins, medicine.symptom, weight-loss, Research Article, medicine.medical_specialty, Waist, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Molecular Genetics, 03 medical and health sciences, Internal medicine, medicine, Genetics, cancer, Humans, Obesity, Genetic Association Studies, VLAG, 030304 developmental biology, Glycemic, Nutrition, Population Biology, lcsh:R, Body Weight, Computational Biology, Human Genetics, populations, medicine.disease, Lipid Metabolism, Cathepsins, Diet, Endocrinology, flip-flop, Glycemic Index, Genetics of Disease, Genetic Polymorphism, glycemic index, lcsh:Q, Basal Metabolism, protein, Weight gain, Body mass index, Population Genetics
Abstract: BACKGROUND/AIMS: Cathepsin S, a protein coded by the CTSS gene, is implicated in adipose tissue biology-this protein enhances adipose tissue development. Our hypothesis is that common variants in CTSS play a role in body weight regulation and in the development of obesity and that these effects are influenced by dietary factors-increased by high protein, glycemic index and energy diets. METHODS: Four tag SNPs (rs7511673, rs11576175, rs10888390 and rs1136774) were selected to capture all common variation in the CTSS region. Association between these four SNPs and several adiposity measurements (BMI, waist circumference, waist for given BMI and being a weight gainer-experiencing the greatest degree of unexplained annual weight gain during follow-up or not) given, where applicable, both as baseline values and gain during the study period (6-8 years) were tested in 11,091 European individuals (linear or logistic regression models). We also examined the interaction between the CTSS variants and dietary factors-energy density, protein content (in grams or in % of total energy intake) and glycemic index-on these four adiposity phenotypes. RESULTS: We found several associations between CTSS polymorphisms and anthropometric traits including baseline BMI (rs11576175 (SNP N degrees 2), p = 0.02, beta = -0.2446), and waist change over time (rs7511673 (SNP N degrees 1), p = 0.01, beta = -0.0433 and rs10888390 (SNP N degrees 3), p = 0.04, beta = -0.0342). In interaction with the percentage of proteins contained in the diet, rs11576175 (SNP N degrees 2) was also associated with the risk of being a weight gainer (p(interaction) = 0.01, OR = 1.0526)-the risk of being a weight gainer increased with the percentage of proteins contained in the diet. CONCLUSION: CTSS variants seem to be nominally associated to obesity related traits and this association may be modified by dietary protein intake.
Published: 2012

22. In and out: adipose tissue lipid turnover in obesity and dyslipidemia

Author: Dominique Langin, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, medicine.medical_specialty, 030309 nutrition & dietetics, business.industry, Physiology, Adipose tissue, White adipose tissue, Cell Biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Obesity, Article, 03 medical and health sciences, Endocrinology, Internal medicine, medicine, business, Molecular Biology, Dyslipidemia, 030304 developmental biology
Abstract: Adipose tissue mass is determined by the storage and removal of triglycerides in adipocytes. Little is known, however, about adipose lipid turnover in humans in health and pathology. To study this in vivo, lipid age was determined by measuring nuclear bomb test-derived 14C in adipocyte lipids. We report that during the average ten year life span of human adipocytes, triglycerides are renewed six times. Lipid age is independent of adipocyte size, is very stable across a wide range of adult ages and does not differ between genders. Adipocyte lipid turnover, however, is strongly related to conditions with disturbed lipid metabolism. In obesity, triglyceride removal rate from fat tissue is decreased and the amount of triglycerides stored each year is increased. In contrast, both lipid removal and storage rates are decreased in non-obese patients diagnosed with the most common hereditary form of dyslipidemia, familial combined hyperlipidemia. Lipid removal rate is positively correlated with the capacity of adipocytes to break down triglycerides, as assessed through lipolysis and is inversely related to insulin resistance. Our data support a mechanism in which adipocyte lipid storage and removal play different roles in health and pathology. High storage but low triglyceride removal promotes fat tissue accumulation and obesity. Reduction of both triglyceride storage and removal decreases lipid shunting through adipose tissue and thus promotes dyslipidemia. We identify adipocyte lipid turnover as a novel target for prevention and treatment of metabolic disease.
Published: 2011

23. Genetic association and gene expression analysis identify FGFR1 as a new susceptibility gene for human obesity

Author: Anne Bouloumié, Karine Clément, Hong Jiao, Dominique Langin, Mikael Rydén, Anders Hamsten, Pilar Galan, Magdalena Taube, Ingrid Dahlman, Anna Benrick, Cyrille Debard, Chantal Simon, Martine Laville, John-Olov Jansson, Angela Silveira, Caroline Hansson, Corneliu Henegar, Tomas Axelsson, Peter Arner, Juha Kere, Hubert Vidal, Karin Dahlman-Wright, Anke Hinney, Niklas Mejhert, Suzanne L. Dickson, Department of Biosciences and Nutrition, Karolinska Institutet [Stockholm], Clinical Research Centre, Karolinska University Hospital [Stockholm], Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg]-University of Gothenburg ( GU ), Régulations métaboliques, nutrition et diabètes - UM55 ( RMND UM55 ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Hospices Civils de Lyon ( HCL ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Atherosclerosis Research Unit, Karolinska Institutet [Stockholm]-Department of Medicine Solna-Cardiovascular Genetics Group, Unité de Recherche en Epidémiologie Nutritionnelle ( UREN ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire d'épidémiologie et de santé publique, Université Louis Pasteur - Strasbourg I, Institut de médecine moléculaire de Rangueil ( I2MR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of medical sciences, Uppsala University-Molecular Medicine-Science for Life Laboratory, Department of child and adolescent psychiatry, Universität Duisburg-Essen [Essen], Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg]-University of Gothenburg (GU), Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Sahlgrenska Academy at University of Gothenburg [Göteborg], Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Department of Biosciences and Nutrition [Karolinska Insitutet, Sueden] (BioNut), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Nutrition Humaine d'Ile-de-France (CRNH-IDF), Institut National de la Recherche Agronomique (INRA)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Science for Life Laboratory [Solna], Royal Institute of Technology [Stockholm] (KTH ), AFA Insurance, Swedish Heart and Lung Foundation, Swedish Research Council [8691], Novo Nordic Foundation, Swedish Diabetes Association, Knut and Alice Wallenberg Foundation, Stockholm County Council [562183], European Commission [LSHM-CT-2005-018734, ADAPT FP7-Health-2007-A], Direction de la Recherche Clinique/Assistance Publique-Hopitaux de Paris, Programmes Hospitaliers de Recherche Clinique [AOR 02076], Le site de l'Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques, region Ile de France, Swedish Medical Research Council [VR k2007-54x-20328-013], European Union [FP7-HEALTH-2009-241592, FP7-KBBE-2009-3-245009], ALF Goteborg [SU7601], Swedish Foundation for Strategic Research [A305-188], German Ministry of Education and Research (NGFNplus) [01GS0820], Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
Subjects: Male, Fibroblast Growth Factor, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Messenger, Medizin, Adipose tissue, Appetite, Biochemistry, Rats, Sprague-Dawley, 0302 clinical medicine, Endocrinology, Odds Ratio, Child, media_common, 2. Zero hunger, 0303 health sciences, education.field_of_study, Blotting, Reverse Transcriptase Polymerase Chain Reaction, Skeletal, Single Nucleotide, Adipose Tissue, Muscle, Female, Western, Type 1, Receptor, Adult, medicine.medical_specialty, Adolescent, Animals, Chi-Square Distribution, European Continental Ancestry Group, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Hypothalamus, Obesity, Polymorphism, RNA, Rats, Sprague-Dawley, media_common.quotation_subject, Population, Blotting, Western, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Context (language use), Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Internal medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Receptor, Fibroblast Growth Factor, Type 1, education, Muscle, Skeletal, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, business.industry, Biochemistry (medical), Odds ratio, Fat cell differentiation, medicine.disease, stomatognathic diseases, business
Abstract: International audience; CONTEXT: Previous studies suggest a role for fibroblast growth factor receptor 1 (FGFR1) in the regulation of energy balance. OBJECTIVE: Our objective was to investigate whether FGFR1 is an obesity gene by genetic association and functional studies. DESIGN: The study was designed to genotype common FGFR1 single-nucleotide polymorphisms (SNP) in large cohorts, confirm significant results in additional cohorts, and measure FGFR1 expression in human adipose tissue and in rodent hypothalamus. SETTING: General community and referral centers for specialized care was the setting for the study. PARTICIPANTS: We genotyped FGFR1 SNP in 2438 obese and 2115 lean adults and 985 obese and 532 population-based children. Results were confirmed in 928 obese and 2738 population-based adults and 487 obese and 441 lean children. Abdominal sc adipose tissue was investigated in 202 subjects. We also investigated diet-induced, obese fasting, and fed rats. MAIN OUTCOME MEASURES: We analyzed the association between FGFR1 SNP and obesity. In secondary analyses, we related adipose FGFR1 expression to genotype, obesity, and degree of fat cell differentiation and related hypothalamic FGFR1 to energy balance. RESULTS: FGFR1 rs7012413*T was nominally associated with obesity in all four cohorts; metaanalysis odds ratio = 1.17 (95% confidence interval = 1.10-1.25), and P = 1.8 × 10(-6), which was P = 7.0 × 10(-8) in the recessive model. rs7012413*T was associated with FGFR1 expression in adipose tissue (P < 0.0001). In this organ, but not in skeletal muscle, FGFR1 mRNA (P < 0.0001) and protein (P < 0.05) were increased in obesity. In rats, hypothalamic expression of FGFR1 declined after fasting (P < ]0.001) and increased after diet-induced obesity (P < 0.05). CONCLUSIONS: FGFR1 is a novel obesity gene that may promote obesity by influencing adipose tissue and the hypothalamic control of appetite.
Published: 2011

24. Macrophage gene expression is related to obesity and the metabolic syndrome in human subcutaneous fat as well as in visceral fat

Author: Pauline Decaunes, Balbine Roussel, Jean-José Maoret, Marion Combes, Michaela Siklova-Vitkova, Nathalie Viguerie, Anne Bouloumié, T Vedral, Zuzana Kovacova, Jindra Hejnova, Dominique Langin, Virginie Bourlier, Michaela Kovacikova, Vladimir Stich, Eva Klimcakova, Franco-czech Laboratory for clinical research on obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of surgery, University Hospital Kralovské Vinohrady, and Simon, Marie Francoise
Subjects: Macrophage, Endocrinology, Diabetes and Metabolism, Adipose tissue, Overweight, 0302 clinical medicine, MESH: Metabolic Syndrome X, Gene expression, MESH: Obesity, Visceral fat, Cells, Cultured, 2. Zero hunger, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Middle Aged, Metabolic syndrome, Real-time polymerase chain reaction, Adipose Tissue, MESH: Young Adult, Female, medicine.symptom, MESH: Adipose Tissue, MESH: Cells, Cultured, Adult, medicine.medical_specialty, 030209 endocrinology & metabolism, Intra-Abdominal Fat, Biology, Young Adult, 03 medical and health sciences, Insulin resistance, MESH: Subcutaneous Fat, Internal medicine, Diabetes mellitus, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Internal Medicine, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, MESH: Overweight, MESH: Intra-Abdominal Fat, Aged, 030304 developmental biology, Inflammation, MESH: Humans, Macrophages, Subcutaneous fat, nutritional and metabolic diseases, MESH: Macrophages, MESH: Adult, medicine.disease, Human adipose tissue, Endocrinology, MESH: Female
Abstract: International audience; AIMS/HYPOTHESIS: Our goal was to identify a set of human adipose tissue macrophage (ATM)-specific markers and investigate whether their gene expression in subcutaneous adipose tissue (SAT) as well as in visceral adipose tissue (VAT) is related to obesity and to the occurrence of the metabolic syndrome. METHODS: ATM-specific markers were identified by DNA microarray analysis of adipose tissue cell types isolated from SAT of lean and obese individuals. We then analysed gene expression of these markers by reverse transcription quantitative PCR in paired samples of SAT and VAT from 53 women stratified into four groups (lean, overweight, obese and obese with the metabolic syndrome). Anthropometric measurements, euglycaemic-hyperinsulinaemic clamp, blood analysis and computed tomography scans were performed. RESULTS: A panel of 24 genes was selected as ATM-specific markers based on overexpression in ATM compared with other adipose tissue cell types. In SAT and VAT, gene expression of ATM markers was lowest in lean and highest in the metabolic syndrome group. mRNA levels in the two fat depots were negatively correlated with glucose disposal rate and positively associated with indices of adiposity and the metabolic syndrome. CONCLUSIONS/INTERPRETATION: In humans, expression of ATM-specific genes increases with the degree of adiposity and correlates with markers of insulin resistance and the metabolic syndrome to a similar degree in SAT and in VAT.
Published: 2011

25. A distinct adipose tissue gene expression response to caloric restriction predicts 6-mo weight maintenance in obese subjects

Author: Claus Holst, M. Ramzi Temanni, Marleen A. van Baak, Véronique Pelloux, Celia G. Walker, Dominique Langin, Teodora Handjieva-Darlenska, Dimitris K. Babalis, Arne Astrup, Jean-Daniel Zucker, Karine Clément, J. Alfredo Martínez, David M. Mutch, Wim H. M. Saris, Adriana Márquez-Quiñones, Tune H. Pers, Nathalie Viguerie, Simon, Marie Francoise, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Human Health and Nutritional Sciences, University of Guelph, Center for Biological Sequence Analysis [Lyngby], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Institute of Preventive Medicine, Copenhagen University Hospital, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Fédératif de Recherche Bio-médicale Institution (IFR150), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), the Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), Department of Internal Medicine, University Hospital of Heraklion, Nutrition Research Centre (NUTRIM), Maastricht University [Maastricht], National Multiprofile Transport Hospital, Human Nutrition Research, Medical Research Council, Department of Human Nutrition, Faculty of Life Science [Copenhagen], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Technical University of Denmark [Lyngby] ( DTU ), Service Nutrition, Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut Français pour la Nutrition - IFN-Centre de Recherche en Nutrition Humaine - CRNH-Ile de France-CHU Pitié-Salpêtrière [APHP], Institut Fédératif de Recherche Bio-médicale, Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-IFR 150, Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Universidad de Navarra [Pamplona] ( UNAV ), Nutrition Research Centre ( NUTRIM ), Faculty of Life Sciences-University of Copenhagen ( KU ), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Technical University of Denmark [Lyngby] (DTU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-IFR150, and University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)
Subjects: Weight loss, Calorie, medicine.medical_treatment, MESH : Insulin, [SDV]Life Sciences [q-bio], Gene Expression, Medicine (miscellaneous), Adipose tissue, PROTEIN, REGAIN, MESH : Analysis of Variance, Weight Gain, 0302 clinical medicine, Insulin Secretion, Insulin, MESH: Obesity, MESH : Female, 0303 health sciences, Glucose tolerance test, Nutrition and Dietetics, MESH: Middle Aged, medicine.diagnostic_test, MESH : Gene Expression Regulation, MESH : Weight Gain, Middle Aged, MESH : Adult, MESH: Gene Expression Regulation, [SDV] Life Sciences [q-bio], BODY-WEIGHT, Gene xxpression, MESH : Subcutaneous Fat, MESH: Young Adult, MESH: Weight Gain, DIETS, Female, MESH : Obesity, medicine.symptom, SENSITIVITY, INTERVENTIONS, Adult, medicine.medical_specialty, MESH : Caloric Restriction, MESH: Gene Expression, MESH: Glucose Tolerance Test, Caloric restriction, Subcutaneous Fat, MESH : Young Adult, 030209 endocrinology & metabolism, MESH: Insulin, Biology, INSULIN-SECRETION, MESH : Glucose Tolerance Test, Young Adult, 03 medical and health sciences, MESH: Weight Loss, MESH: Subcutaneous Fat, Internal medicine, Diabetes mellitus, MESH: Analysis of Variance, Weight Loss, medicine, EXTRACELLULAR-MATRIX, Humans, MESH : Middle Aged, Obesity, Weight gain, Caloric Restriction, 030304 developmental biology, Analysis of Variance, MESH: Caloric Restriction, MESH: Humans, MESH : Humans, MESH: Adult, Glucose Tolerance Test, medicine.disease, MESH : Gene Expression, ENERGY-INTAKE, Endocrinology, Gene Expression Regulation, MESH : Weight Loss, GAIN, MESH: Female
Abstract: Background: Weight loss has been shown to reduce risk factors associated with cardiovascular disease and diabetes; however, successful maintenance of weight loss continues to pose a challenge. Objective: The present study was designed to assess whether changes in subcutaneous adipose tissue (scAT) gene expression during a low-calorie diet (LCD) could be used to differentiate and predict subjects who experience successful short-term weight maintenance from subjects who experience weight regain. Design: Forty white women followed a dietary protocol consisting of an 8-wk LCD phase followed by a 6-mo weight-maintenance phase. Participants were classified as weight maintainers (WMs; 0‐10% weight regain) and weight regainers (WRs; 50‐100% weight regain) by considering changes in body weight during the 2 phases. Anthropometric measurements, bioclinical variables, and scAT gene expression were studied in all individuals before and after the LCD. Energy intake was estimated by using 3-d dietary records. Results: No differences in body weight and fasting insulin were observed between WMs and WRs at baseline or after the LCD period. The LCD resulted in significant decreases in body weight and in several plasma variables in both groups. WMs experienced a significant reduction in insulin secretion in response to an oralglucose-tolerance test after the LCD; in contrast, no changes in insulin secretion were observed in WRs after the LCD. An ANOVA of scAT gene expression showed that genes regulating fatty acid metabolism, citric acid cycle, oxidative phosphorylation, and apoptosis were regulated differently by the LCD in WM and WR subjects. Conclusion: This study suggests that LCD-induced changes in insulin secretion and scAT gene expression may have the potential to predict successful short-term weight maintenance. This trial was registered at clinicaltrials.gov as NCT00390637. Am J Clin Nutr 2011;94:1399‐409.
Published: 2011

26. Dietary intervention-induced weight loss decreases macrophage content in adipose tissue of obese women

Author: Zuzana Kovacova, Anne Bouloumié, Z Hněvkovská, Jan Polak, Vladimir Stich, Lenka Rossmeislová, J. Hejnova, Eva Klimcakova, Michaela Siklova-Vitkova, Dominique Langin, Coralie Sengenès, Michaela Kovacikova, Magda Bajzova, Department of Sports Medicine, Charles University [Prague] (CU), Franco-Czech Laboratory for Clinical Research on Obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Second Internal Medicine Department, Vinohrady Teaching Hospital, Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Simon, Marie Francoise
Subjects: Adult, Chemokine CXCL5, medicine.medical_specialty, Diet, Reducing, Adipose Tissue, White, Endocrinology, Diabetes and Metabolism, Adipose tissue macrophages, Population, Vesicular Transport Proteins, Down-Regulation, Medicine (miscellaneous), Adipose tissue, 030209 endocrinology & metabolism, Real-Time Polymerase Chain Reaction, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Weight loss, Internal medicine, Weight Loss, medicine, Humans, Longitudinal Studies, Obesity, education, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, education.field_of_study, Nutrition and Dietetics, business.industry, Gene Expression Profiling, Macrophages, Body Weight, Flow Cytometry, medicine.disease, 3. Good health, C-Reactive Protein, medicine.anatomical_structure, Endocrinology, Female, medicine.symptom, business, CD163, Subcutaneous tissue
Abstract: International audience; Objective:Accumulation of adipose tissue macrophages (ATMs) is observed in obesity and may participate in the development of insulin resistance and obesity-related complications. The aim of our study was to investigate the effect of long-term dietary intervention on ATM content in human adipose tissue.Design:We performed a multi-phase longitudinal study.Subjects and measurements:A total of 27 obese pre-menopausal women (age 39+/-2 years, body mass index 33.7+/-0.5 kg m(-2)) underwent a 6-month dietary intervention consisting of two periods: 4 weeks of very low-calorie diet (VLCD) followed by weight stabilization composed of 2 months of low-calorie diet and 3to 4 months of weight maintenance diet. At baseline and at the end of each dietary period, samples of subcutaneous adipose tissue (SAT) were obtained by needle biopsy and blood samples were drawn. ATMs were determined by flow cytometry using combinations of cell surface markers. Selected cytokine and chemokine plasma levels were measured using enzyme-linked immunosorbent assay. In addition, in a subgroup of 16 subjects, gene expression profiling of macrophage markers in SAT was performed using real-time PCR.Results:Dietary intervention led to a significant decrease in body weight, plasma insulin and C-reactive protein levels. After VLCD, ATM content defined by CD45+/14+/206+ did not change, whereas it decreased at the end of the intervention. This decrease was associated with a downregulation of macrophage marker mRNA levels (CD14, CD163, CD68 and LYVE-1 (lymphatic vessel endothelial hyaluronan receptor-1)) and plasma levels of monocyte-chemoattractant protein-1 (MCP-1) and CXCL5 (chemokine (C-X-C motif) ligand 5). During the whole dietary intervention, the proportion of two ATM subpopulations distinguished by the CD16 marker was not changed.Conclusion:A 6-month weight-reducing dietary intervention, but not VLCD, promotes a decrease in the number of the whole ATM population with no change in the relative distribution of ATM subsets.International Journal of Obesity advance online publication, 8 June 2010; doi:10.1038/ijo.2010.112.
Published: 2010

27. TCF7L2 rs7903146-macronutrient interaction in obese individuals' responses to a 10-wk randomized hypoenergetic diet

Author: Katrine Grau, J. Alfredo Martínez, Eva Klimcakova, Ian A. Macdonald, Jean-Michel Oppert, Dominique Langin, Oluf Pedersen, Claus Holst, Ellen E. Blaak, Stéphane Cauchi, Arne Astrup, Thorkild I. A. Sørensen, Peter Arner, Wim H. M. Saris, Stephan Rössner, Philippe Froguel, Institute of Preventive Medicine, Copenhagen University Hospital-Centre for HealthSociet, Genomic Medicine, Imperial College London-Hammersmith Hospital, Center for Pharmacogenomics, Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Department of Drug Design and Pharmacology [Copenhagen] (ILF), University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Institut de biologie de Lille - UMS 3702 (IBL), Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Department of Human Nutrition, Faculty of Life Science [Copenhagen], Department of PhysiologyNutrition, Universidad de Navarra [Pamplona] (UNAV), Department of Human Biology NutritionToxicology, Maastricht University [Maastricht]-Research Institute Maastricht, Service de nutrition, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital de l'Hôtel-Dieu, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Obesity Unit Department of Medicine Karolinska University Hospital Huddinge, Karolinska Institutet [Stockholm]-Karolinska University Hospital Huddinge, School of Biomedical Science, University of Nottingham Medical School-Queen's Medical Centre, Department of Sports Medicine, Charles University [Prague] (CU)-Third Faculty of Medicine-Centre of Preventive Medicine, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Steno Diabetes Center, Hagedorn Research Institute, Department of Biomedical Sciences [Copenhagen], Faculty of Health Science, Department of Drug Design and Pharmacology [Copenhagen] (ILF), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: Blood Glucose, Male, MESH: Dietary Carbohydrates, MESH: Chi-Square Distribution, endocrine system diseases, Medicine (miscellaneous), Type 2 diabetes, SUSCEPTIBILITY, Polymerase Chain Reaction, GLUCOSE, MESH: Genotype, 0302 clinical medicine, Weight loss, Insulin, MESH: Obesity, 2. Zero hunger, RISK, MESH: Diet, Reducing, 0303 health sciences, INSULIN-RESISTANCE, Nutrition and Dietetics, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH: DNA, HOMEOSTASIS MODEL ASSESSMENT, Middle Aged, MESH: Basal Metabolism, MESH: Dietary Fats, HIGH-FAT, Female, medicine.symptom, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, Adult, medicine.medical_specialty, Diet, Reducing, Genotype, TYPE-2 DIABETIC-PATIENTS, 030209 endocrinology & metabolism, MESH: Insulin, Biology, GENE POLYMORPHISMS, Polymorphism, Single Nucleotide, 03 medical and health sciences, Insulin resistance, BETA-CELL FUNCTION, Internal medicine, Diabetes mellitus, medicine, Dietary Carbohydrates, Humans, Resting energy expenditure, Obesity, 030304 developmental biology, Chi-Square Distribution, MESH: Humans, nutritional and metabolic diseases, MESH: Adult, MESH: Polymerase Chain Reaction, DNA, medicine.disease, Dietary Fats, MESH: Male, ENERGY-INTAKE, Endocrinology, Basal metabolic rate, MESH: Blood Glucose, Basal Metabolism, TCF7L2, MESH: Female, MESH: TCF Transcription Factors
Abstract: International audience; BACKGROUND: Transcription factor 7-like 2 (TCF7L2) rs7903146 associates with type 2 diabetes and may operate via impaired glucagon-like peptide 1 secretion, which is stimulated more by fat than by carbohydrate ingestion. OBJECTIVE: The objective was to examine the interaction between TCF7L2 rs7903146 and dietary fat and carbohydrate [high-fat, low-carbohydrate: 40-45% of energy as fat (HF); compared with low-fat, high-carbohydrate: 20-25% of energy as fat (LF)] in obese individuals' responses to a 10-wk hypoenergetic diet (-600 kcal/d). DESIGN: European, obese participants (n = 771) were randomly assigned to receive an HF or an LF diet. Body weight, fat mass (FM), fat-free mass (FFM), waist circumference (WC), resting energy expenditure (REE), fasting fat oxidation in percentage of REE (FatOx), homeostasis model assessed insulin release (HOMA-beta), and HOMA-insulin resistance (HOMA-IR) were determined at baseline and after the intervention; 739 individuals were genotyped for rs7903146. RESULTS: Average weight loss was 6.9 kg with the LF and 6.6 kg with the HF (difference between diets, NS) diet. Among individuals who were homozygous for the T-risk allele, those in the HF diet group experienced smaller weight losses (Deltaweight) (2.6 kg; P = 0.009; n = 622), smaller DeltaFFM (1.6 kg; P = 0.027; n = 609), smaller DeltaWC (3.3 cm; P = 0.010; n = 608), and a smaller DeltaHOMA-IR (1.3 units; P = 0.004; n = 615) than did the LF diet group. For C allele carriers, there were no differences between the HF and LF diet groups. For the HF diet group, each additional T allele was associated with a reduced loss of FM (0.67 kg; P = 0.019; n = 609). TCF7L2 rs7903146 was not associated with DeltaREE, DeltaFatOx, DeltaHOMA-beta, or dropout. CONCLUSION: Our results suggest that obese individuals who are homozygous for the TCF7L2 rs7903146 T-risk allele are more sensitive to LF than to HF weight-loss diets.
Published: 2010

28. cyclin G2 and adipocyte differentiation

Author: Joan Vendrell, Xavier Escoté, Victor Aguilar, Jean-Sébastien Annicotte, Lluis Fajas, Dominique Langin, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Endocrinology and Diabetes Unit, University Hospital of Tarragona, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), and This work was supported by grants from FRM, INCA, and ANR.
Subjects: Male, PPARγ, Cyclin D, Cyclin A, Cyclin B, Fluorescent Antibody Technique, Cultured Cyclin G2/genetics/*metabolism Fluorescent Antibody Technique Immunoprecipitation Male Mice Mice, Mice, Endocrinology, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Up-Regulation, Adipocytes, MESH: Animals, MESH: Fluorescent Antibody Technique, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Cyclin, 0303 health sciences, Adipogenesis, biology, Reverse Transcriptase Polymerase Chain Reaction, 030302 biochemistry & molecular biology, MESH: Cyclin G2, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Up-Regulation, Cell biology, MESH: Cells, Cultured, 3T3-L1 Cells Adipocytes/cytology/*metabolism Adipogenesis/*genetics Animals Cells, Cyclin G2, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Transfection, Article, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Cyclin-dependent kinase, 3T3-L1 Cells, Animals, Immunoprecipitation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, MESH: Adipocytes, 030304 developmental biology, MESH: Immunoprecipitation, MESH: Transfection, Inbred C57BL PPAR gamma/genetics/*metabolism Reverse Transcriptase Polymerase Chain Reaction Transfection Up-Regulation, MESH: 3T3-L1 Cells, MESH: Male, Mice, Inbred C57BL, PPAR gamma, MESH: PPAR gamma, biology.protein, Cyclin-dependent kinase complex, MESH: Adipogenesis, Cyclin A2
Abstract: International audience; Cell cycle regulators such as cyclins, cyclin-dependent kinases, or retinoblastoma protein play important roles in the differentiation of adipocytes. In the present paper, we investigated the role of cyclin G2 as a positive regulator of adipogenesis. Cyclin G2 is an unconventional cyclin which expression is up-regulated during growth inhibition or apoptosis. Using the 3T3-F442A cell line, we observed an up-regulation of cyclin G2 expression at protein and mRNA levels throughout the process of cell differentiation, with a further induction of adipogenesis when the protein is transiently overexpressed. We show here that the positive regulatory effects of cyclin G2 in adipocyte differentiation are mediated by direct binding of cyclin G2 to peroxisome proliferator-activated receptor γ (PPARγ), the key regulator of adipocyte differentiation. The role of cyclin G2 as a novel PPARγ coactivator was further demonstrated by chromatin immunoprecipitation assays, which showed that the protein is present in the PPARγ-responsive element of the promoter of aP2, which is a PPARγ target gene. Luciferase reporter gene assays, showed that cyclin G2 positively regulates the transcriptional activity of PPARγ. The role of cyclin G2 in adipogenesis is further underscored by its increased expression in mice fed a high-fat diet. Taken together, our results demonstrate a novel role for cyclin G2 in the regulation of adipogenesis.
Published: 2010

29. Chronic TNFalpha and cAMP pre-treatment of human adipocytes alter HSL, ATGL and perilipin to regulate basal and stimulated lipolysis

Author: Aline Mairal, Véronic Bezaire, Corinne Lefort, Dominique Langin, Rodica Anesia, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: medicine.medical_specialty, Hormone-sensitive lipase, Perilipin-1, Lipolysis, Biophysics, Biology, Biochemistry, Adipose triglyceride lipase, 03 medical and health sciences, 0302 clinical medicine, Protein kinase A, Structural Biology, Internal medicine, Lipid droplet, Genetics, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, TNFα, Adipocytes, Cyclic AMP, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphorylation, Molecular Biology, 030304 developmental biology, 0303 health sciences, Tumor Necrosis Factor-alpha, Colforsin, Cell Biology, Lipase, Sterol Esterase, Phosphoproteins, Endocrinology, 030220 oncology & carcinogenesis, Perilipin, Carrier Proteins, Forskolin
Abstract: International audience; We examined the effects of chronic TNFalpha and dibutyryl-cAMP (Db-cAMP) pre-treatment on the lipolytic machinery of human hMADS adipocytes. TNFalpha decreased adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) protein content and triglycerides (TG)-hydrolase activity but increased basal lipolysis due to a marked reduction in perilipin (PLIN) protein content. Conversely, Db-cAMP increased ATGL and HSL protein content but prevented PLIN phosphorylation, the net result being accentuated basal lipolysis. In forskolin-stimulated conditions, TNFalpha and Db-cAMP pre-treatment decreased stimulated TG-hydrolase activity and impaired PLIN phosphorylation. Together, this resulted in a severely attenuated response to forskolin-stimulated lipolysis.
Published: 2009

30. Lipolysis and lipid mobilization in human adipose tissue

Author: Dominique Langin, Max Lafontan, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: medicine.medical_specialty, Lipolysis, Adipose tissue, 030209 endocrinology & metabolism, Biology, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Lipid droplet, Adipocyte, Internal medicine, medicine, Animals, Humans, Hormone metabolism, Obesity, Triglycerides, 030304 developmental biology, 0303 health sciences, Biological Transport, Lipid metabolism, Cell Biology, Hormones, Endocrinology, Adipose Tissue, chemistry, Adipose triglyceride lipase, Perilipin
Abstract: International audience; Triacylglycerol (TAG) stored in adipose tissue (AT) can be rapidly mobilized by the hydrolytic action of the three main lipases of the adipocyte. The non-esterified fatty acids (NEFA) released are used by other tissues during times of energy deprivation. Until recently hormone-sensitive lipase (HSL) was considered to be the key rate-limiting enzyme responsible for regulating TAG mobilization. A novel lipase named adipose triglyceride lipase/desnutrin (ATGL) has been identified as playing an important role in the control of fat cell lipolysis. Additionally perilipin and other proteins of the surface of the lipid droplets protecting or exposing the TAG core of the droplets to lipases are also potent regulators of lipolysis. Considerable progress has been made in understanding the mechanisms of activation of the various lipases. Lipolysis is under tight hormonal regulation. The best understood hormonal effects on AT lipolysis concern the opposing regulation by insulin and catecholamines. Heart-derived natriuretic peptides (i.e., stored in granules in the atrial and ventricle cardiomyocytes and exerting stimulating effects on diuresis and natriuresis) and numerous autocrine/paracrine factors originating from adipocytes and other cells of the stroma-vascular fraction may also participate in the regulation of lipolysis. Endocrine and autocrine/paracrine factors cooperate and lead to a fine regulation of lipolysis in adipocytes. Age, anatomical site, sex, genotype and species differences all play a part in the regulation of lipolysis. The manipulation of lipolysis has therapeutic potential in the metabolic disorders frequently associated with obesity and probably in several inborn errors of metabolism.
Published: 2009

31. Effect of hyperinsulinemia and very-low-calorie diet on interstitial cytokine levels in subcutaneous adipose tissue of obese women

Author: Zuzana Hnevkovska, Vladimir Stich, Dominique Langin, Jindra Hejnova, Lenka Rossmeislová, Zuzana Kovacova, Michaela Siklova-Vitkova, Eva Klimcakova, Michaela Kovacikova, Magda Bajzova, Jan Polak, Jindra Vrzalova, Charles University [Prague] (CU), 3rd Faculty of Medicine, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: Adult, medicine.medical_specialty, Microdialysis, Physiology, Endocrinology, Diabetes and Metabolism, food.diet, Subcutaneous Fat, Adipokine, Adipose tissue, 030209 endocrinology & metabolism, Type 2 diabetes, 03 medical and health sciences, 0302 clinical medicine, food, Interstitial fluid, Weight loss, Physiology (medical), Internal medicine, Hyperinsulinism, Hyperinsulinemia, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Homeostasis, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, Chemokine CCL2, 030304 developmental biology, Caloric Restriction, 2. Zero hunger, 0303 health sciences, business.industry, Interleukin-6, Interleukin-8, Middle Aged, medicine.disease, 3. Good health, Very low calorie diet, Endocrinology, Glucose Clamp Technique, Cytokines, Female, medicine.symptom, Chemokines, Insulin Resistance, business
Abstract: International audience; Aim: Type II diabetes and obesity are associated with an enhanced release of a number of adipocytokines. Hyperinsulinemia - frequently present in type II diabetes and obesity - might be one of the drivers of the enhanced production of adipocytokines. The aim of this study was to investigate the interstitial levels of cytokines in subcutaneous adipose tissue (SCAT) in response to hyperinsulinemia and the effect of weight-reducing hypocaloric diet on this regulation in obese subjects. Methods: 13 obese pre-menopausal women participated in the study. Concentrations of 7 cytokines were measured in plasma and in AT interstitial fluid collected by microdialysis method during euglycemic-hyperinsulinemic clamp and during control infusion of physiological saline. A subgroup of 6 women underwent a 4-week very-low-calorie diet (VLCD). Microdialysis during the clamp was performed before and at the end of VLCD. Results: Hyperinsulinemia induced an increase of monocyte chemoatractant protein (MCP-1) and IL-6 SCAT interstitial and plasma levels, and elevated IL-8 levels in SCAT. The relative changes of IL-6 levels in the dialysate correlated with changes of IL-8 and MCP-1. The interstitial and plasma levels of IL-1beta, IL-10, TNFalpha and plasminogen activator inhibitor (PAI-1) remained unchanged in response to hyperinsulinemia. VLCD resulted in an enhancement of the hyperinsulinemia-induced augmentation of MCP-1, IL-6 and IL-8 interstitial levels. Conclusion: Hyperinsulinemia upregulates the interstitial levels of MCP 1, IL-6 and IL-8 in SCAT in obese women while it does not affect IL-1beta, IL-10, TNFalpha and PAI-1 levels. Hypocaloric diet associated with weight reduction enhances the hyperinsulinemia-induced up-regulation of MCP 1, IL-6 and IL-8 in SCAT. Key words: cytokine, hyperinsulinemia, microdialysis, adipose tissue.
Published: 2009

32. Contribution of Adipose Triglyceride Lipase and Hormone-sensitive Lipase to Lipolysis in hMADS Adipocytes

Author: Peter Arner, Anne-Marie Rodriguez, Rodica Anesia, Jurga Laurencikiene, Amandine Girousse, Dominique Langin, Johan W. E. Jocken, Véronic Bezaire, Gérard Ailhaud, Christian Dani, Aline Mairal, Britta M Stenson, Corinne Lefort, Mikael Rydén, Carole Ribet, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de Signalisation, Biologie du Développement et Cancer, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Simon, Marie Francoise, Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, and CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan
Subjects: medicine.medical_specialty, Lipolysis, Green Fluorescent Proteins, 030209 endocrinology & metabolism, Hormone-sensitive lipase, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Cytosol, 0302 clinical medicine, Internal medicine, Lipid droplet, Adipocytes, medicine, Humans, RNA, Small Interfering, Lipase, Molecular Biology, Cells, Cultured, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Esterification, biology, Fatty acid metabolism, Catabolism, Hydrolysis, Colforsin, Fatty Acids, Fatty acid, Cell Biology, 1-Acylglycerol-3-Phosphate O-Acyltransferase, Sterol Esterase, Metabolism and Bioenergetics, Endocrinology, chemistry, Adipose triglyceride lipase, biology.protein, Energy Metabolism
Abstract: International audience; Lipolysis is the catabolic pathway by which triglycerides are hydrolyzed into fatty acids. Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) have the capacity to hydrolyze in vitro the first ester bond of triglycerides, but their respective contributions to whole cell lipolysis in human adipocytes is unclear. Here, we have investigated the roles of HSL, ATGL, and its coactivator CGI-58 in basal and forskolin-stimulated lipolysis in a human white adipocyte model, the hMADS cells. The hMADS adipocytes express the various components of fatty acid metabolism and show lipolytic capacity similar to primary cultured adipocytes. We show that lipolysis and fatty acid esterification are tightly coupled except in conditions of stimulated lipolysis. Immunocytochemistry experiments revealed that acute forskolin treatment promotes HSL translocation from the cytosol to small lipid droplets and redistribution of ATGL from the cytosol and large lipid droplets to small lipid droplets, resulting in enriched colocalization of the two lipases. HSL or ATGL overexpression resulted in increased triglyceride-specific hydrolase capacity, but only ATGL overexpression increased whole cell lipolysis. HSL silencing had no effect on basal lipolysis and only partially reduced forskolin-stimulated lipolysis. Conversely, silencing of ATGL or CGI-58 significantly reduced basal lipolysis and essentially abolished forskolin-stimulated lipolysis. Altogether, these results suggest that ATGL/CGI-58 acts independently of HSL and precedes its action in the sequential hydrolysis of triglycerides in human hMADS adipocytes.
Published: 2009

33. CXC ligand 5 is an adipose-tissue derived factor that links obesity to insulin resistance

Author: Julien Schmidt, Lluis Fajas, Eric Renard, Gökhan S. Hotamisligil, Dominique Langin, Gwendal Lazennec, Anna Gumà, Irena Iankova, Hiroyasu Yamamoto, Rosario Sanches, Antonio Vidal-Puig, Carine Chavey, Jacques Teyssier, Robert M. Strieter, Bénédicte Jardin-Watelet, Sylviane Lagarrigue, Jean-Sébastien Annicotte, Antoinette Tuthill, Michaela Vitkova, Chikage Mataki, Cyrielle Clapé, Vladimir Stich, Antonio Zorzano, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Métabolisme et cancer, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 (UM1)-IFR3, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Research in Biomedecine, and Departement de Bioquimina Biologia Molecular, Universitat de Barcelona (UB), Department of Sport Medicine and Obesity Unit, Charles University [Prague] (CU), CNRS/Bio-Rad, Centre National de la Recherche Scientifique (CNRS), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de pharmacologie et innovation dans le diabète (CPID), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Department of Medecine, University of Virginia [Charlottesville], Metabolic Research Laboratories, University of Cambridge [UK] (CAM), Harvard School of Public Health, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, This work was supported by grants of INSERM, Fondation pour la Recherche Médicale (équipe FRM), the European Commission (HEPADIP project, Contract LSHM-CT-2005-018734) and ANR (PHYSIO 2006). C.C is granted by Agence National pour la Recherche. GSH is supported by a grant from the National Institutes of Health USA (DK052539)., Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Franco-czech Laboratory for clinical research on obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Modélisation et ingéniérie des systèmes complexes pour le diagnostic (MISCD), BIO-RAD FRANCE HOLDING-Centre National de la Recherche Scientifique (CNRS), University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Le Ster, Yves, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre National de la Recherche Scientifique (CNRS), University of Virginia, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: MESH: Signal Transduction, Chemokine CXCL5, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Physiology, Glucose uptake, HUMDISEASE, Adipose tissue, White adipose tissue, MESH: Thiazolidinediones, Mice, 0302 clinical medicine, Adipose Tissue/cytology/drug effects/*metabolism Animals Chemokine CXCL5/deficiency/genetics/*metabolism Gene Expression Regulation/drug effects Humans *Insulin Resistance Macrophages/drug effects/metabolism Mice Obesity/*metabolism RNA, Messenger/genetics/metabolism Signal Transduction/drug effects Thiazolidinediones/pharmacology Tumor Necrosis Factor-alpha/pharmacology, MESH: Obesity, MESH: Animals, CXC chemokine receptors, Receptor, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Gene Expression Regulation, 3. Good health, MESH: Insulin Resistance, Adipose Tissue, medicine.symptom, MESH: Adipose Tissue, Signal Transduction, medicine.medical_specialty, MESH: Rosiglitazone, MESH: Chemokine CXCL5, 030209 endocrinology & metabolism, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, Rosiglitazone, 03 medical and health sciences, Insulin resistance, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, RNA, Messenger, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, Tumor Necrosis Factor-alpha, Macrophages, MESH: Macrophages, Cell Biology, medicine.disease, Insulin receptor, Endocrinology, Gene Expression Regulation, MESH: Tumor Necrosis Factor-alpha, biology.protein, Thiazolidinediones, Insulin Resistance
Abstract: International audience; We show here high levels of expression and secretion of the chemokine CXC ligand 5 (CXCL5) in the macrophage fraction of white adipose tissue (WAT). Moreover, we find that CXCL5 is dramatically increased in serum of human obese compared to lean subjects. Conversely, CXCL5 concentration is decreased in obese subjects after a weight reduction program, or in obese non-insulin-resistant, compared to insulin-resistant, subjects. Most importantly we demonstrate that treatment with recombinant CXCL5 blocks insulin-stimulated glucose uptake in muscle in mice. CXCL5 blocks insulin signaling by activating the Jak2/STAT5/SOCS2 pathway. Finally, by treating obese, insulin-resistant mice with either anti-CXCL5 neutralizing antibodies or antagonists of CXCR2, which is the CXCL5 receptor, we demonstrate that CXCL5 mediates insulin resistance. Furthermore CXCR2-/- mice are protected against obesity-induced insulin resistance. Taken together, these results show that secretion of CXCL5 by WAT resident macrophages represents a link between obesity, inflammation, and insulin resistance.
Published: 2009

34. Secretion of adiponectin multimeric complexes from adipose tissue explants is not modified by very low calorie diet

Author: Lenka Rossmeislová, Zuzana Hnevkovska, Magda Bajzova, Zuzana Kovacova, Jan Polak, Michaela Vitkova, Dominique Langin, Vladimir Stich, Michaela Kovacikova, Eva Klimcakova, Sports Medicine Department, Third Faculty of Medicine Charles University, Division of Cell and Molecular Biology, Franco-Czech Laboratory for Clinical Research on Obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Internal Medicine Department, Vinohrady Teatching Hospital, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Male, Luminescence, Polymers, Endocrinology, Diabetes and Metabolism, Adipose tissue, Tissue Culture Techniques, 0302 clinical medicine, Endocrinology, Weight loss, Blood plasma, MESH: Obesity, 2. Zero hunger, 0303 health sciences, medicine.diagnostic_test, MESH: Kinetics, MESH: Luminescence, MESH: Molecular Weight, MESH: Waist-Hip Ratio, Biopsy, Needle, MESH: Enzyme-Linked Immunosorbent Assay, General Medicine, MESH: Adiponectin, 3. Good health, MESH: Polymers, Very low calorie diet, Adipose Tissue, Female, Adiponectin, medicine.symptom, MESH: Adipose Tissue, Adult, medicine.medical_specialty, MESH: Biopsy, Needle, food.diet, Blotting, Western, 030209 endocrinology & metabolism, Enzyme-Linked Immunosorbent Assay, Biology, 03 medical and health sciences, MESH: Weight Loss, food, Western blot, Internal medicine, MESH: Body Height, Weight Loss, medicine, Humans, MESH: Blotting, Western, Secretion, Obesity, MESH: Tissue Culture Techniques, 030304 developmental biology, Caloric Restriction, MESH: Caloric Restriction, MESH: Humans, Waist-Hip Ratio, Body Weight, MESH: Adult, medicine.disease, Body Height, MESH: Male, Culture Media, MESH: Body Weight, Molecular Weight, Kinetics, MESH: Culture Media, MESH: Female
Abstract: ObjectiveAdiponectin is a protein abundantly secreted by the adipose tissue (AT). Plasma adiponectin levels are decreased in obese, insulin-resistant, and type 2 diabetic patients. Various multimeric complexes, i.e. high-, middle-, and low-molecular weight isoforms (HMW, MMW and LMW), are present in plasma. Here, we investigated the effect of weight reducing diet on the distribution of adiponectin isoforms in plasma and on their secretion in AT explants from obese subjects.DesignA total of 20 obese subjects (age 37.8±7.3 years, body mass index 33.9±5.0 kg/m2) underwent eight weeks of very low-calorie diet (VLCD). A needle biopsy of subcutaneous abdominal AT and blood samples were taken before and after dietary intervention. AT explants were incubated in culture medium for 4 h. ELISA assay and western blot analyses were used to identify adiponectin complexes in culture media and in plasma.ResultsThe distribution of adiponectin polymers in plasma was different from that secreted in human AT explants. Before VLCD, the relative amount of HMW isoform was 75.5±9.1% of total adiponectin in culture media and 52.2±11.2% in plasma. Despite the diet-induced weight loss and improvement of insulin sensitivity, VLCD neither induced change in total adiponectin level nor in the ratio of HMW to total adiponectin in plasma and in culture media of AT explants.ConclusionsThe profile of adiponectin polymeric isoforms secreted by AT explants into culture media differs from the plasma profile. A dietary intervention leading to weight loss and improvement of insulin sensitivity was not associated with modifications of AT secretion of total or HMW adiponectin.
Published: 2009

35. Regulation of adipose tissue lipolysis revisited

Author: Véronic, Bézaire, Dominique, Langin, Simon, Marie Francoise, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Inflammation, Adipose Tissue, Lipolysis, Adipocytes, White, Humans, Proteins, Obesity, Insulin Resistance, Signal Transduction
Abstract: International audience; Human obesity and its complications are an increasing burden in developed and underdeveloped countries. Adipose tissue mass and the mechanisms that control it are central to elucidating the aetiology of obesity and insulin resistance. Over the past 15 years tremendous progress has been made in several avenues relating to adipose tissue. Knowledge of the lipolytic machinery has grown with the identification of new lipases, cofactors and interactions between proteins and lipids that are central to the regulation of basal and stimulated lipolysis. The dated idea of an inert lipid droplet has been appropriately revamped to that of a dynamic and highly-structured organelle that in itself offers regulatory control over lipolysis. The present review provides an overview of the numerous partners and pathways involved in adipose tissue lipolysis and their interaction under various metabolic states. Integration of these findings into whole adipose tissue metabolism and its systemic effects is also presented in the context of inflammation and insulin resistance.
Published: 2009

36. Contribution of energy restriction and macronutrient composition to changes in adipose tissue gene expression during dietary weight-loss programs in obese women

Author: Claus Holst, Nathalie Vega, Moira A. Taylor, J. Alfredo Martínez, Eva Klimcakova, Thorkild I. A. Sørensen, Dominique Langin, Sébastien Déjean, Jean M. Oppert, Peter Arner, Hubert Vidal, Nathalie Viguerie, Karine Clément, Frédéric Capel, Wim H. M. Saris, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Recherche sur les obésités, CHU Toulouse [Toulouse]-Laboratoire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service d'anatomie et cytologie pathologiques [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Franco-Czech Laboratory for Clinical Research on Obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine Lyon-Sud, FACULTE DE LYON, Centre de Recherche en Nutrition Humaine, Hospices Civils de Lyon (HCL), Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Institut de Mathématiques de Toulouse UMR5219 (IMT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Department of Midicine Karolinska Institute, Karolinska University Hospital Huddinge, Department of Sports Medicine of Charles University, Faculty of Medicine Charles University, Department of Physiology and nutrition University of Navarra, Universidad de Navarra [Pamplona] (UNAV), Department of Human Biology Nutrition and Toxicology Research Institute, Maastricht University [Maastricht], The Netherlands Institute of Preventive Medicine, Institute of Preventive Medicine, School of Biomedical Sciences Queen's Medical Center, University of Nottingham Medical School, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse, Charles University [Prague]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Department of Nutrition and Endocrinology AP / HP, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut de médecine moléculaire de Rangueil ( I2MR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), IFR 31 Louis Bugnard ( IFR 31 ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Charles University [Prague]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hospices Civils de Lyon ( HCL ), Régulations métaboliques, nutrition et diabètes - UM55 ( RMND UM55 ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Hospices Civils de Lyon ( HCL ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ), Institut de Mathématiques de Toulouse UMR5219 ( IMT ), Université Toulouse 1 Capitole ( UT1 ) -Université Toulouse - Jean Jaurès ( UT2J ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-PRES Université de Toulouse-Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ), Universidad de Navarra [Pamplona] ( UNAV ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Endocrinologie, maladies métaboliques et nutrition [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Transcription, Genetic, Endocrinology, Diabetes and Metabolism, MESH: Energy Intake, Biochemistry, Body Mass Index, 0302 clinical medicine, Endocrinology, Gene expression, MESH: Genetic Variation, MESH : Adaptor Proteins, Signal Transducing, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Addipose tissue, Reducing, MESH: Mitochondrial Proteins, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, MESH : Oligonucleotide Array Sequence Analysis, Adipose Tissue, Body Composition, MESH: Adipose Tissue, medicine.medical_specialty, Diet, Reducing, MESH : Body Composition, MESH : Adipose Tissue, MESH: Body Mass Index, MESH : Receptors, Glucocorticoid, 03 medical and health sciences, MESH: Weight Loss, Genetic, Humans, MESH : Fatty Acid-Binding Proteins, MESH : Mitochondrial Proteins, MESH: Adaptor Proteins, Signal Transducing, MESH: Humans, MESH : Humans, Signal Transducing, Genetic Variation, MESH: Adult, Autophagy-Related Protein 8 Family, MESH: Body Composition, medicine.disease, Obesity, MESH : Energy Metabolism, MESH : Body Mass Index, Energy intake, Body mass index, MESH: Female, Candidate gene, MESH: Receptors, Glucocorticoid, Clinical Biochemistry, Adipose tissue, Blood lipids, Glucocorticoid, Weight loss, Sirtuin 3, Receptors, MESH : RNA, Sirtuins, MESH: Obesity, MESH : Female, Nutrición y dietética [Ciencias de la Salud], MESH : Diet, Reducing, 2. Zero hunger, MESH : Sirtuins, MESH: Diet, Reducing, Microfilament Proteins, MESH: Energy Metabolism, Adaptor Proteins, MESH : Adult, MESH: Sirtuins, MESH : Obesity, Female, medicine.symptom, Transcription, Adult, MESH : Microfilament Proteins, 030209 endocrinology & metabolism, Context (language use), Biology, Fatty Acid-Binding Proteins, MESH: Fatty Acid-Binding Proteins, Mitochondrial Proteins, MESH: Microfilament Proteins, Receptors, Glucocorticoid, MESH : Genetic Variation, MESH: RNA, Internal medicine, Weight Loss, medicine, 030304 developmental biology, Adaptor Proteins, Signal Transducing, MESH: Transcription, Genetic, Biochemistry (medical), MESH : Transcription, Genetic, MESH : Energy Intake, Diet, MESH: Oligonucleotide Array Sequence Analysis, RNA, MESH : Weight Loss, Energy Intake, Energy Metabolism
Abstract: Context: Hypoenergetic diets are used to reduce body fat mass and metabolic risk factors in obese subjects. The molecular changes in adipose tissue associated with weight loss and specifically related to the dietary composition are poorly understood. Objective: We investigated adipose tissue gene expression from human obese women according to energy deficit and, the fat and carbohydrate content of the diet. Design & setting: Obese subjects recruited among 8 European clinical centers followed 10 weeks of either a low fat (high carbohydrate) or a moderate fat (low carbohydrate) hypoenergetic diet. Subjects: Two sets of 47 women in each dietary arm were selected among 648 subjects matched for anthropometric and biological parameters. Main Outcome Measure: We measured adipose tissue gene expression changes in one set using a candidate gene approach. The other set was used to survey 24469 transcripts using DNA microarrays. Results were analyzed using dedicated statistical methods. Diet-sensitive regulations were confirmed on the other set of subjects. Results: The two diets induced similar weight loss and similar changes for most of the biological variables except for components of the blood lipid profile. A thousand genes were regulated by energy restriction. We validated an effect of the fat-to-carbohydrate ratio for five genes (FABP4, NR3C1, SIRT3, FNTA and GABARAPL2) with increased expression during the moderate fat diet. Conclusions: Energy restriction had a more pronounced impact on variations in human adipose tissue gene expression than macronutrient composition. The macronutrient-sensitive regulation of a subset of genes may influence adipose tissue function and metabolic response. AD - INSERM, U858, Laboratoire de Recherches sur les Obesites, Institut de Medecine Moleculaire de Rangueil, Toulouse; Universite Paul Sabatier, Institut Louis Bugnard IFR31, Toulouse; Centre Hospitalier Universitaire de Toulouse, France; Franco-Czech Laboratory for Clinical Research on Obesity, Prague, Czech Republic; INSERM, UMR -870; INRA U-1235; Faculte de Medecine Lyon-Sud universite de Lyon 1; Centre de Recherche en Nutrition Humaine, Hospices civils de Lyon; Lyon, France; Institut de Mathematiques de Toulouse UMR 5219, Universite Paul-Sabatier, Toulouse, France; Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Sports Medicine, Centre of Preventive Medicine, Third Faculty of Medicine, Charles University, Prague, Czech Republic; Franco-Czech Laboratory for Clinical Research on Obesity, Prague, Czech Republic; Department of Physiology and Nutrition, University of Navarra, Pamplona, Spain; Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands; Institute of Preventive Medicine, Centre for Health and Society, Copenhagen University Hospital, Copenhagen, Denmark; School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham Medical School, Nottingham, United Kingdom; INSERM, Nutriomique U872 (Team 7), 75004 Paris, France; Universites Pierre et Marie Curie-Paris6, UMR-S 872, Cordelier Research Center & Paris Descartes, 75006 Paris; and Assistance Publique/Hopitaux de Paris (AP-HP), Pitie Salpetriere Hospital, Nutrition and Endocrinology department, 75013 Paris, France.
Published: 2008

37. Evidence for an important role of CIDEA in human cancer cachexia

Author: Britta M Stenson, Elisabet Arvidsson Nordström, Jurga Laurencikiene, Peter Arner, Johan Permert, Thorhallur Agustsson, Mikael Rydén, Dominique Langin, Bengt Isaksson, Simon, Marie Francoise, Departments of Medicine, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Departments of Surgery, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Male, Cancer Research, Cachexia, White adipose tissue, Body Mass Index, chemistry.chemical_compound, Mice, Adipocyte, Neoplasms, Adipocytes, MESH: Neoplasms, MESH: Animals, Phosphorylation, PRDM16, MESH: Aged, MESH: Middle Aged, Fatty Acids, MESH: Energy Metabolism, Middle Aged, Pyruvate dehydrogenase complex, MESH: Fatty Acids, MESH: Glucose, Oncology, MESH: Adipose Tissue, White, Female, Adult, medicine.medical_specialty, Pyruvate dehydrogenase kinase, Adipose Tissue, White, PDK4, Pyruvate Dehydrogenase Complex, Biology, Protein Serine-Threonine Kinases, MESH: Protein-Serine-Threonine Kinases, MESH: Body Mass Index, MESH: Pyruvate Dehydrogenase Complex, Internal medicine, 3T3-L1 Cells, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Lipolysis, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, MESH: Mice, MESH: Adipocytes, Aged, MESH: RNA, Messenger, MESH: Humans, MESH: Phosphorylation, MESH: Apoptosis Regulatory Proteins, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, MESH: Adult, medicine.disease, MESH: 3T3-L1 Cells, MESH: Male, Endocrinology, Glucose, chemistry, MESH: Cachexia, Apoptosis Regulatory Proteins, Energy Metabolism, MESH: Female
Abstract: Loss of fat mass in cancer cachexia is linked to increased adipocyte lipolysis; however, the fate of the excess fatty acids (FA) generated by lipolysis is not known. We investigated if the adipocyte-specific gene cell death–inducing DNA fragmentation factor-α–like effector A (CIDEA) could be involved. CIDEA mRNA expression was assessed in s.c. white adipose tissue from 23 cancer cachexia patients, 17 weight-stable cancer patients, and 8 noncancer patients. CIDEA was also overexpressed in adipocytes in vitro. CIDEA expression was increased in cancer cachexia (P < 0.05) and correlated with elevated levels of FAs and reported weight loss (P < 0.001). CIDEA overexpression in vitro increased FA oxidation 2- to 4-fold (P < 0.01), decreased glucose oxidation by 40% (P < 0.01), increased the expression of pyruvate dehydrogenase kinase (PDK) 1 and PDK4 (P < 0.01), and enhanced the phosphorylation (inactivation) of the pyruvate dehydrogenase complex (PDC). Inactivation of PDC facilitates FA oxidation by favoring the metabolism of FAs over glucose to acetyl-CoA. In accordance with the in vitro data, PDK1 and PDK4 expression correlated strongly with CIDEA expression in white adipose tissue (P < 0.001). We conclude that CIDEA is involved in adipose tissue loss in cancer cachexia and this may, at least in part, be due to its ability to inactivate PDC, thereby switching substrate oxidation in human fat cells from glucose to FAs. [Cancer Res 2008;68(22):9247–54]
Published: 2008

38. Effects of TCF7L2 polymorphisms on obesity in European populations

Author: Michel Marre, Fritz F. Horber, Katrine Grau, David Meyre, Alex Duval, Christian Dina, Christine Proença, Hélène Choquet, Guillaume Charpentier, Thorkild I. A. Sørensen, Stéphane Cauchi, Philippe Froguel, Ruth Gutierrez-Aguilar, Beverley Balkau, Dominique Langin, Frédéric Capel, Natascha Potoczna, Simon, Marie Francoise, Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Preventive Medicine, Copenhagen University Hospital, Instabilité des microsatellites et cancers [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Déterminants génétiques du diabète de type 2 et de ses complications vasculaires ((U 695)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Obesity Centre, Klinik Lindberg, Obesity Center Klink Lindberg, Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital de Corbeil, Genomic Medicine, Imperial College London-Hammersmith Hospital, Medical Research Council G0600331, Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Instabilité des microsatellites et cancers [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], and Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, endocrine system diseases, Polymorphism, Single Nucleotide/*genetics, Endocrinology, Diabetes and Metabolism, TCF Transcription Factors/*genetics/metabolism, Medicine (miscellaneous), Adipose tissue, Type 2 diabetes, Body Mass Index, 0302 clinical medicine, Endocrinology, Risk Factors, MESH: Risk Factors, Medicine, MESH: Obesity, MESH: Aged, 0303 health sciences, education.field_of_study, Nutrition and Dietetics, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, MESH: European Continental Ancestry Group, Middle Aged, MESH: Case-Control Studies, Pedigree, Diabetes Mellitus, Type 2/ethnology/etiology, Female, France, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, MESH: Diabetes Mellitus, Type 2, Adult, medicine.medical_specialty, endocrine system, MESH: Pedigree, Population, Subcutaneous Fat, Genetic Predisposition to Disease/ethnology/genetics, 030209 endocrinology & metabolism, Polymorphism, Single Nucleotide, White People, MESH: Body Mass Index, 03 medical and health sciences, MESH: Subcutaneous Fat, Internal medicine, Humans, Genetic Predisposition to Disease, Obesity, Allele, education, Alleles, 030304 developmental biology, Aged, MESH: Humans, business.industry, MESH: Alleles, Case-control study, nutritional and metabolic diseases, Obesity/complications/ethnology/*genetics, MESH: Adult, Odds ratio, medicine.disease, MESH: Male, European Continental Ancestry Group/ethnology/genetics, MESH: France, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Diabetes Mellitus, Type 2, Case-Control Studies, business, TCF7L2, MESH: Female, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH: TCF Transcription Factors, Subcutaneous Fat/metabolism
Abstract: 1930-7381 (Print) Journal Article Research Support, Non-U.S. Gov't; International audience; The transcription factor 7-like 2 (TCF7L2) rs7903146 T allele was previously associated with type 2 diabetes (T2D) and decreased BMI whereas haplotypes carrying the rs7903146 C and rs10885406 A alleles (HapA) were associated with increased BMI. The functional relevance of TCF7L2 polymorphisms and their effects on T2D and obesity remained to be further investigated.In white European populations, we found that the rs7903146 T allele was more associated with T2D in 3,547 non-obese individuals (odds ratio (OR) = 1.88 (1.69-2.10)) than in 1,110 class III obese subjects (OR = 1.24 (1.03-1.50)). No direct effect of the rs7903146 C allele and HapA was found on any form of obesity in 3,507 normal glucose tolerant (NGT) individuals, 1,106 pedigrees with familial obesity and 5,512 individuals from the French general population. However, in T2D subjects, the rs7903146 C allele was less prevalent in the 1,111 non-obese individuals (55.2%) compared to 659 class III obese subjects (67.5% OR = 1.69 (1.46-1.95)). Functional studies showed that the rs7903146 T allele is less prone to be bound by protein factors than the C allele in 3T3-L1, HepG2 and beta-TC3 cell lines and that TCF7L2 expression decreases in subcutaneous adipose tissue from NGT obese T/T carriers under calorie restriction.In conclusion, TCF7L2 is not a risk factor for obesity in European populations, but its effect on T2D risk is modulated by obesity. Furthermore, our data suggest that the rs7903146 T allele may be possibly functional and associated with a nominal decrease in TCF7L2 expression in adipose tissue of individuals under calorie restriction.
Published: 2008

39. Regulation of inflammation-related genes in human adipose tissue

Author: Dominique Langin, Karine Clément, Service de nutrition, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital de l'Hôtel-Dieu, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Franco-Czech Laboratory for Clinical Research on Obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital de l'Hôtel-Dieu, Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de médecine moléculaire de Rangueil ( I2MR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Charles University [Prague]-Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: MESH: Inflammation, Panniculitis, Adipose tissue, MESH : Panniculitis, 0302 clinical medicine, Weight loss, Macrophage, Medicine, MESH: Obesity, MESH : Macrophages, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, MESH : Gene Expression Regulation, MESH: Panniculitis, MESH: Gene Expression Regulation, 3. Good health, Adipose Tissue, MESH : Obesity, medicine.symptom, Inflammation Mediators, MESH: Adipose Tissue, Calorie restriction, MESH: Inflammation Mediators, 030209 endocrinology & metabolism, Inflammation, Context (language use), Physical exercise, MESH : Adipose Tissue, MESH : Inflammation Mediators, 03 medical and health sciences, MESH: Gene Expression Profiling, Internal Medicine, Humans, Serum amyloid A, Obesity, 030304 developmental biology, MESH : Inflammation, MESH: Humans, business.industry, Tumor Necrosis Factor-alpha, MESH : Gene Expression Profiling, Gene Expression Profiling, Macrophages, MESH : Humans, MESH: Macrophages, Gene Expression Regulation, MESH: Tumor Necrosis Factor-alpha, Immunology, business
Abstract: International audience; The identification of a moderate increase in circulating inflammatory factors in obese subjects, the description of changes in inflammatory gene expression in adipose tissue (AT) and the discovery that macrophage cells infiltrate AT are observations contributing to the concept that human obesity is a chronic inflammatory illness. This concept has led to some revision of the physiopathology of obesity and of its related metabolic and cardiovascular co-morbidities. Low-grade inflammation in the AT and the subsequent production of specific biomarkers could actually link expanded fat mass to obesity complications. This review aims at providing an overview of the current knowledge brought up by human gene expression studies, notably those performed on a large scale in AT depots. The regulation of specific biomarkers related to inflammation and putative new candidates (i.e. cathepsins and serum amyloid A) is discussed in the context of weight loss programmes based on calorie restriction and physical exercise. The foreseen clinical and technological challenges are also summarized.
Published: 2007

40. Resistance to high-fat-diet-induced obesity and sexual dimorphism in the metabolic responses of transgenic mice with moderate uncoupling protein 3 overexpression in glycolytic skeletal muscles

Author: Jacques Rami, Geneviève Tavernier, Aline Mairal, François Crampes, Frédéric Capel, Jean A. Boutin, Claire Tiraby, C. Pujol, Dominique Langin, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Division de Pharmacologie Moléculaire et Cellulaire, Institut de Recherches Servier, Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Blood Glucose, Male, RNA, Messenger/genetics, Endocrinology, Diabetes and Metabolism, Ion Channels, Mice, 0302 clinical medicine, Uncoupling Protein 3, Uncoupling protein, Glycolysis, MESH: Animals, Inner mitochondrial membrane, UCP3, 2. Zero hunger, Sex Characteristics, 0303 health sciences, MESH: Muscle, Skeletal, Mitochondrial Proteins/*genetics, MESH: Mitochondria, Muscle, MESH: Mitochondrial Proteins, MESH: Gene Expression Regulation, Mitochondria, Muscle/*physiology, MESH: Insulin Resistance, MESH: Dietary Fats, MESH: Glycolysis, Female, MESH: Sex Characteristics, Genetically modified mouse, medicine.medical_specialty, Ratón, MESH: Mice, Transgenic, Mice, Transgenic, Dietary Fats, Biology, Mitochondrial Proteins, 03 medical and health sciences, In vivo, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Internal Medicine, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Muscle, Skeletal/*physiology, Muscle, Skeletal, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, Insulin Resistance, MESH: Male, Mitochondria, Muscle, Ion Channels/*genetics, Sexual dimorphism, Endocrinology, Gene Expression Regulation, MESH: Ion Channels, MESH: Blood Glucose, Blood Glucose/*metabolism, MESH: Female, 030217 neurology & neurosurgery
Abstract: 0012-186X (Print) 0012-186X (Linking) Journal Article Research Support, Non-U.S. Gov't; International audience; AIMS/HYPOTHESIS: Uncoupling protein (UCP) 3 is a mitochondrial inner membrane protein expressed predominantly in glycolytic skeletal muscles. Its role in vivo remains poorly understood. The aim of the present work was to produce a mouse model with moderate overproduction and proper fibre-type distribution of UCP3. METHODS: Transgenic mice were created with a 16 kb region encompassing the human UCP3 gene. Mitochondrial uncoupling was investigated on permeabilised muscle fibres. Changes in body weight, adiposity and glucose or insulin tolerance were assessed in mice fed chow and high-fat diets. Indirect calorimetry was used to determine whole-body energy expenditure and substrate utilisation. RESULTS: Transgenic mice showed a twofold increase in UCP3 protein levels specifically in glycolytic muscles. Mitochondrial respiration revealed an increase of uncoupling in glycolytic but not in oxidative muscles. Transgenic mice gained less weight than wild-type littermates due to lower adipose tissue accretion when fed a high-fat diet. Animals showed a sexual dimorphism in metabolic responses. Female transgenic mice were more glucose-sensitive than wild-type animals, while male transgenic mice with high body weights had impaired glucose and insulin tolerance. Measurements of RQs in mice fed chow and high-fat diets suggested an impairment of metabolic flexibility in transgenic male mice. CONCLUSIONS/INTERPRETATION: Our data show that physiological overproduction of UCP3 in glycolytic muscles results in mitochondrial uncoupling, resistance to high-fat diet-induced obesity and sex specificity regarding insulin sensitivity and whole-body substrate utilisation.
Published: 2007

41. Hormone-sensitive lipase expression and activity in relation to lipolysis in human fat cells

Author: Jacques Grober, Vanessa van Harmelen, Peter Arner, Dominique Langin, Signy Reynisdottir, Cecilia Holm, Valérie Large, Institut Louis Bugnard, and Large, Valerie
Subjects: Male, Hormone-sensitive lipase, White adipose tissue, Biochemistry, MESH: Isoproterenol, Adenylyl cyclase, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Adipocyte, Adipocytes, MESH: Obesity, MESH: Genetic Variation, MESH: Cell Size, 0303 health sciences, Forskolin, MESH: Sterol Esterase, biology, MESH: Kinetics, Immunochemistry, MESH: Molecular Weight, food and beverages, Female, catecholamines, Adult, medicine.medical_specialty, Lipolysis, 030209 endocrinology & metabolism, QD415-436, In Vitro Techniques, 03 medical and health sciences, white adipose tissue, Internal medicine, medicine, Humans, MESH: Lipolysis, Obesity, RNA, Messenger, Lipase, MESH: Adipocytes, 030304 developmental biology, Cell Size, MESH: RNA, Messenger, MESH: In Vitro Techniques, MESH: Humans, Activator (genetics), MESH: Immunochemistry, Isoproterenol, Genetic Variation, MESH: Adult, Cell Biology, Sterol Esterase, β-adrenoceptors, MESH: Male, Molecular Weight, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Kinetics, chemistry, lipid mobilization, biology.protein, MESH: Female, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Hormone-sensitive lipase (HSL) catalyzes the rate-limiting step in adipocyte lipolysis. The activity of HSL is thought to be primarily regulated by reversible phosphorylation. However, the regulation of HSL activity by pretranslational mechanisms has been poorly studied. The present studies were undertaken to explore the relationship between the levels of HSL protein and mRNA expressions and the lipolytic capacity. The study was performed in human abdominal subcutaneous adipocytes with identical sizes but having either a high (HL) or low (LL) lipolytic capacity (n = 16). Basal and maximal lipolysis induced by catecholamines, an adenylyl cyclase activator forskolin, and a cyclic AMP analogue dibutyryl cAMP were 50% lower in LL- in comparison with HL-fat cells (P < 0.05 or better). No differences in drug sensitivity were found. HSL activity and quantity were about 50% lower in LL- compared with HL-fat cells (P < 0.05). Moreover, the mRNA ratio between HSL and γ-actin was 35% lower in LL-compared with HL-fat cells (P < 0.05). There was a strong linear correlation between the protein and enzymatic HSL measurements (r2 = 0.91). In addition, the maximum lipolytic capacity was significantly correlated with HSL activity (r 2 = 0.75) and HSL protein amount (r 2 = 0.64). It is concluded that hormone-sensitive lipase (HSL) expression, measured either as total HSL protein by Western blot analysis or as total amount of activatable HSL enzyme, is a major determinant of the maximum lipolytic capacity of human fat cells. In addition, HSL protein expression is at least, in part, determined by HSL mRNA expression.—Large, V., P. Arner, S. Reynisdottir, J. Grober, V. Van Harmelen, C. Holm, and D. Langin. Hormone-sensitive lipase expression and activity in relation to lipolysis in human fat cells.
Published: 1998

42. ARN messagers spécifiant la lipoprotéine-lipase, la synthétase des acides gras et la lipase hormono-sensible dans le tissu adipeux de brebis et de vaches sous-nutries puis réalimentées

Author: Muriel Bonnet, Yannick Faulconnier, Jean-François Hocquette, Leroux, C., Dominique Langin, Patrice Martin, Yves Chilliard, Laboratoire de recherches sur la sous-nutrition des ruminants, Institut National de la Recherche Agronomique (INRA), Laboratoire de recherches sur la croissance et les métabolismes des herbivores, Unité de recherche Génétique Biochimique et Cytogénétique (LGBC), and ProdInra, Migration
Subjects: sous nutrition, [SDV.SA.SPA]Life Sciences [q-bio]/Agricultural sciences/Animal production studies, [SDV.SA.SPA] Life Sciences [q-bio]/Agricultural sciences/Animal production studies
Abstract: "Chantier qualité spécifique "Auteurs Externes" département de Génétique animale : uniquement liaison auteur au référentiel HR-Access "; International audience
Published: 1998

43. Messenger RNAs encoding lipoprotein lipase, fatty acid synthase and hormone-sensitive lipase in the adipose tissue of underfed-refed ewes and cows

Author: Yves Chilliard, Christine Leroux, Muriel Bonnet, Yannick Faulconnier, Jeanne Flechet, Patrice Martin, Dominique Langin, Jean-François Hocquette, and Revues Inra, Import
Subjects: medicine.medical_specialty, 030309 nutrition & dietetics, Malic enzyme, Adipose tissue, Hormone-sensitive lipase, 03 medical and health sciences, Internal medicine, Gene expression, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Animals, RNA, Messenger, Northern blot, Lipase, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Lipoprotein lipase, Sheep, biology, food and beverages, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Sterol Esterase, Lipids, Lipoprotein Lipase, Fatty acid synthase, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, Adipose Tissue, Food, biology.protein, Cattle, Female, Fatty Acid Synthases, Food Deprivation, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: The mechanisms involved in the nutritional regulation of genes encoding lipogenic (lipoprotein lipase (LPL) and fatty acid synthase (FAS)) and lipolytic (hormone-sensitive lipase (HSL)) enzymes were investigated by comparing the levels of the corresponding mRNAs in the adipose tissue (AT) of underfed or underfed-refed ewes and cows. Refeeding sharply increased LPL and FAS activities (19-25- and 6-8-fold, respectively) and moderately increased (2-4 fold) the activities of glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme (ME) and glyce- rol-3-phosphate dehydrogenase (G3PDH). Northern blot analysis revealed three LPL transcripts and a single FAS transcript in cow and ewe AT. A single HSL mRNA was detected in cow AT and two transcripts in ewe AT. Refeeding sharply increased LPL and FAS mRNA levels, while restriction slightly increased (cows) or had no effect (ewes) on the HSL mRNA levels. This sug- gests that nutritional factors regulate sharply the expression of LPL and FAS genes by pretrans- lational mechanisms, but less clearly that of HSL gene. @ Inra/Elsevier, Paris
Published: 1998

44. Influence of prolactin on in vivo and in vitro lipolysis in rabbits

Author: Max Lafontan, L. Fortun-Lamothe, Dominique Langin, Station de recherches cunicoles, Institut National de la Recherche Agronomique (INRA), and ProdInra, Migration
Subjects: Ovine prolactin, Glycerol, endocrine system, medicine.medical_specialty, Lipolysis, [SDV]Life Sciences [q-bio], Immunology, 030209 endocrinology & metabolism, [INFO] Computer Science [cs], Biology, Oxytocin, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Adrenocorticotropic Hormone, In vivo, Internal medicine, medicine, Adipocytes, Animals, [INFO]Computer Science [cs], ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Pharmacology, 0303 health sciences, Single injection, Sterol Esterase, Prolactin, In vitro, 3. Good health, [SDV] Life Sciences [q-bio], Hyperprolactinemia, Endocrinology, chemistry, Growth Hormone, Female, Rabbits, hormones, hormone substitutes, and hormone antagonists
Abstract: Three experiments were conducted to assess the influence of prolactin on lipolysis in rabbits. In vivo, a single injection of 1 mg of ovine prolactin induces increased plasma glycerol and nonesterified fatty acids concentrations within 30 min (P0.01). On the contrary, in vitro, oPRL did not stimulate glycerol release in isolated adipocytes at physiological concentrations (under 10(-8) M). In a third experiment, the effect of chronic hyperprolactinemia on the adrenergic control of lipolysis was studied (daily subcutaneous injections of 1 mg ovine prolactin for 12 days). The weight of perirenal adipose tissue at the end of the period of injections was 27% lower in the prolactin-injected (PRL) rabbits than in the control (CTL) rabbits (88 +/- 15 g vs. 120 +/- 25 g; P0.05). Food intake during the period of injections was 28% lower in the PRL group than in the CTL group (177 +/- 21 g/d vs. 246 +/- 13 g/d; P0.05). Basal glycerol release was 157% higher in adipocytes from PRL rabbits than in those from CTL rabbits (P0.05). Stimulation of lipolysis with different adrenergic agonists was similar in both groups. These results suggested an indirect influence of prolactin on adipose tissue lipolysis in rabbits, but mechanisms implicated in this effect remain to be elucidated.
Published: 1996

45. Regulation of hormone-sensitive lipase gene expression in 3T3-F442A and BFC-1 adipocytes

Author: J. Grober, Dominique Langin, Claude Forest, E. Plee, and Revues Inra, Import
Subjects: 3t3 f442a, 0402 animal and dairy science, Hormone-sensitive lipase, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, 04 agricultural and veterinary sciences, Biology, 040201 dairy & animal science, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Biochemistry, Gene expression, [SDV.BDD] Life Sciences [q-bio]/Development Biology, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology
Abstract: International audience
Published: 1996

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