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1. Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells

Author

Fourcade, Olivier, Simon, Marie-Francoise, Viode, Cecile, Rugani, Nathalie, Leballe, Francois, Ragab, Ashraf, Fournie, Bernard, Sarda, Louis, and Chap, Hugues

Subjects
Phospholipases -- Research, Phospholipids -- Physiological aspects, Sphingolipids -- Physiological aspects, Biological sciences
Abstract

Nonpancreatic secretory phospholipase A2 (sPLA2) may be involved in cell signaling during the inflammatory response. This enzyme degrades phospholipids in microvesicles shed from Ca2+-loaded erythrocytes, apparently increasing in activity during sphingomyelin hydrolysis. Phosphatidic acid is converted to the lipid mediator lysophosphatidic acid by sPLA2.

Published
1995

4. Structure-activity analysis of the effects of lysophosphatidic acid on platelet aggregation

Author

Gueguen, Genevieve, Gaige, Bernadette, Grevvy, Jean-Michel, Rogalle, Pierre, Bellan, Jacques, Wilson, Michele, Klaebe, Alain, Pont, Frederic, Simon, Marie-Francoise, and Chap, Hugues

Subjects
Blood platelets -- Receptors, Structure-activity relationships (Biochemistry) -- Research, Coagulation -- Research, Biological sciences, Chemistry
Abstract

Research was conducted to examine the effects of various lysophosphatidic acid (1-acyl-sn-glycero-3-phosphate, or LPA) analogues on human platelets. Results confirm the lack of stereospecificity of platelet LPA receptors. Findings also indicate that platelets possess a pharmacologically distinct receptor whose molecular identity still remains to be established. It is concluded that the unique series of compounds may be used for further characterization of other endogenous or recombinant LPA receptors.

Published
1999

7. Monoamine oxidases as sources of oxidants in the heart

Author

Jeanne Mialet-Perez, Nina Kaludercic, Angelo Parini, Fabio Di Lisa, Nazareno Paolocci, Simon, Marie Francoise, Neuroscience Institute, National Research Council (CNR), 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), Johns Hopkins Medical Institutions, Johns Hopkins University School of Medicine, Department of Biomedical Sciences, Università degli Studi di Padova = University of Padua (Unipd), and Universita degli Studi di Padova

Subjects
medicine.medical_specialty, Monoamine oxidase, Aldehyde dehydrogenase, Mitochondrion, medicine.disease_cause, Article, Internal medicine, medicine, Animals, Humans, Monoamine Oxidase, Molecular Biology, Aldehydes, biology, Chemistry, Myocardium, Oxidative deamination, Hydrogen Peroxide, Oxidants, 3. Good health, Oxidative Stress, Endocrinology, Monoamine neurotransmitter, biology.protein, Catecholamine, Serotonin, Cardiology and Cardiovascular Medicine, Oxidative stress, medicine.drug
Abstract

International audience; Oxidative stress can be generated at several sites within the mitochondria. Among these, monoamine oxidase (MAO) has been described as a prominent source. MAOs are mitochondrial flavoenzymes responsible for the oxidative deamination of catecholamines, serotonin and biogenic amines, and during this process they generate H2O2 and aldehyde intermediates. The role of MAO in cardiovascular pathophysiology has only recently gathered some attention since it has been demonstrated that both H2O2 and aldehydes may target mitochondrial function and consequently affect function and viability of the myocardium. In the present review, we will discuss the role of MAO in catecholamine and serotonin clearance and cycling in relation to cardiac structure and function. The relevant contribution of each MAO isoform (MAO-A or -B) will be discussed in relation to mitochondrial dysfunction and myocardial injury. Finally, we will examine both beneficial effects of their pharmacological or genetic inhibition along with potential adverse effects observed at baseline in MAO knockout mice, as well as the deleterious effects following their over-expression specifically at cardiomyocyte level. This article is part of a Special Issue entitled "Redox Signalling in the Cardiovascular System".

Published
2014

8. Transition from metabolic adaptation to maladaptation of the heart in obesity: role of apelin

Author

Angelo Parini, Rodica Anesia, Oksana Kunduzova, Philippe Valet, Camille Foussal, Denis Calise, Estelle Wanecq, Danièle Daviaud, Olivier Lairez, Chiara Alfarano, Camille Attané, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), 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, ANEXPLO, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), 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-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-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)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), 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 National de la Santé et de la Recherche Médicale (INSERM)-Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from the National Institute of Health and Medical Research (INSERM), Fondation Lefoulon-Delalande, Fondation de France, Région Midi-Pyrénées and Association Française d'Etudes et de Recherches sur l'Obésité., Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Ecole Nationale Vétérinaire de Toulouse (ENVT), 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), Simon, Marie Francoise, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE)

Subjects
Cardiac function curve, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Carbohydrate metabolism, Diet, High-Fat, Muscle hypertrophy, Mice, Adipokines, Internal medicine, medicine, Myocyte, Animals, Myocytes, Cardiac, Obesity, 2. Zero hunger, Pressure overload, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Heart Failure, Nutrition and Dietetics, business.industry, Myocardium, Metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Apelin, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Heart failure, Intercellular Signaling Peptides and Proteins, Original Article, business, Oxidation-Reduction
Abstract

International audience; Background/Objectives:Impaired energy metabolism is the defining characteristic of obesity-related heart failure. The adipocyte-derived peptide apelin has a role in the regulation of cardiovascular and metabolic homeostasis and may contribute to the link between obesity, energy metabolism and cardiac function. Here we investigate the role of apelin in the transition from metabolic adaptation to maladaptation of the heart in obese state.Methods:Adult male C57BL/6J, apelin knock-out (KO) or wild-type mice were fed a high-fat diet (HFD) for 18 weeks. To induce heart failure, mice were subjected to pressure overload after 18 weeks of HFD. Long-term effects of apelin on fatty acid (FA) oxidation, glucose metabolism, cardiac function and mitochondrial changes were evaluated in HFD-fed mice after 4 weeks of pressure overload. Cardiomyocytes from HFD-fed mice were isolated for analysis of metabolic responses.Results:In HFD-fed mice, pressure overload-induced transition from hypertrophy to heart failure is associated with reduced FA utilization (P

Published
2014

9. Determinants of Flow-Mediated Outward Remodeling in Female Rodents

Author

Bertrand Toutain, Jean-François Arnal, Daniel Henrion, Laurent Loufrani, Anne-Laure Guihot, Vincent Procaccio, Linda Grimaud, Emilie Vessieres, Françoise Lenfant, Kahena Tarhouni, Institut de Recherche en Génie Civil et Mécanique (GeM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-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), and Simon, Marie Francoise

Subjects
Aging, medicine.medical_specialty, Time Factors, Nitric Oxide Synthase Type III, medicine.drug_class, Ovariectomy, Estrogen receptor, 030204 cardiovascular system & hematology, Biology, 03 medical and health sciences, 0302 clinical medicine, In vivo, Internal medicine, medicine, Animals, Rats, Wistar, Extracellular Signal-Regulated MAP Kinases, Ventricular remodeling, 030304 developmental biology, 0303 health sciences, Estradiol, Superoxide Dismutase, Estrogen Receptor alpha, Blood flow, medicine.disease, Arterial occlusion, Mesenteric Arteries, Rats, Vasodilation, medicine.anatomical_structure, Endocrinology, Regional Blood Flow, Estrogen, Ovariectomized rat, Female, Vascular Resistance, Endothelium, Vascular, Stress, Mechanical, Cardiology and Cardiovascular Medicine, Artery
Abstract

Objective— Flow (shear stress)-mediated outward remodeling (FMR) of resistance arteries is a key adaptive process allowing collateral growth after arterial occlusion but declining with age. 17-β-estradiol (E2) has a key role in this process through activation of estrogen receptor α (ERα). Thus, we investigated the impact of age and timing for estrogen efficacy on FMR. Approach and Results— Female rats, 3 to 18 months old, were submitted to surgery to increase blood flow locally in 1 mesenteric artery in vivo. High-flow and normal-flow arteries were collected 2 weeks later for in vitro analysis. Diameter increased by 27% in high-flow arteries compared with normal-flow arteries in 3-month-old rats. The amplitude of remodeling declined with age (12% in 18-month-old rats) in parallel with E2 blood level and E2 substitution failed restoring remodeling in 18-month-old rats. Ovariectomy of 3-, 9-, and 12-month-old rats abolished FMR, which was restored by immediate E2 replacement. Nevertheless, this effect of E2 was absent 9 months after ovariectomy. In this latter group, ERα and endothelial nitric oxide synthase expression were reduced by half compared with age-matched rats recently ovariectomized. FMR did not occur in ERα −/− mice, whereas it was decreased by 50% in ERα +/− mice, emphasizing the importance of gene dosage in high-flow remodeling. Conclusions— E2 deprivation, rather than age, leads to decline in FMR, which can be prevented by early exogenous E2. However, delayed E2 replacement was ineffective on FMR, underlining the importance of timing of this estrogen action.

Published
2014

10. Immune Cell Toll-like Receptor 4 Mediates the Development of Obesity- and Endotoxemia-Associated Adipose Tissue Fibrosis

Author

Jacques Grober, Vladimir Stich, Philippe Gui, Corinne Lefort, Geneviève Tavernier, Virginie Bourlier, Isabelle K. Vila, Lenka Rossmeislová, Lucile Mir, Katie Louche, Anne Bouloumié, Nathalie Viguerie, Pierre Marie Badin, Balbine Roussel, Alexia Zakaroff-Girard, Dominique Langin, Cedric Moro, Marie Adeline Marques, Laurent Monbrun, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), 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, Franco-Czech Laboratory for Clinical Research on Obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), PHOTONIQUE (XLIM-PHOTONIQUE), XLIM (XLIM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), Sérine protéases et physiopathologie de l'unité neurovasculaire, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Forschungsinstitut für Rationalisierung e.V. (FIR) an der RWTH Aachen, Franco-czech Laboratory for clinical research on obesity, 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), I.K.V. was supported by fellowships from Inserm and Région Midi-Pyrénées. This work was supported by grants from Agence Nationale de la Recherche (LIPOB and OBELIP projects), Région Midi-Pyrénées, Fondation pour la Recherche Médicale, and the Commission of the European Communities (projects DIABAT, HEPADIP, and ADAPT) (to D.L.) and by a grant from Société Francophone du Diabète (to C.M.)., Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Departament Geodinàmica i Geofísica, Facultat de Geologia, Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Charles University [Prague], Charles University [Prague]-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), 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 des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Hôpital de Rangueil-Institut National de la Santé et de la Recherche Médicale ( INSERM ), PHOTONIQUE ( XLIM-PHOTONIQUE ), XLIM ( XLIM ), Université de Limoges ( UNILIM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Limoges ( UNILIM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Charles University [Prague]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), U858 Institut de médecine moléculaire de Rangueil (I2MR), and Institut National de la Santé et de la Recherche Médicale

Subjects
Lipopolysaccharides, MESH: Signal Transduction, MESH: Inflammation, MESH : Toll-Like Receptor 4, Adipose tissue, MESH : Adipocytes, MESH : Lipopolysaccharides, Mice, chemistry.chemical_compound, Fibrosis, Adipocyte, Adipocytes, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Obesity, MESH: Animals, lcsh:QH301-705.5, Mice, Inbred C3H, Toll-like receptor, MESH : Diet, High-Fat, MESH: Toll-Like Receptor 4, 3. Good health, MESH: Insulin Resistance, Adipose Tissue, MESH: Fibrosis, MESH : Fibrosis, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : Obesity, MESH : Insulin Resistance, MESH: Adipose Tissue, Signal Transduction, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Adipose tissue macrophages, Biology, Diet, High-Fat, MESH : Adipose Tissue, General Biochemistry, Genetics and Molecular Biology, Immune system, MESH : Mice, Inbred C3H, Internal medicine, MESH : Mice, medicine, Animals, Humans, Obesity, MESH: Mice, Inbred C3H, MESH: Mice, MESH: Adipocytes, Inflammation, MESH : Signal Transduction, MESH : Inflammation, MESH: Humans, MESH : Endotoxemia, MESH : Humans, 3T3-L1, medicine.disease, MESH : Disease Models, Animal, Endotoxemia, Toll-Like Receptor 4, Disease Models, Animal, MESH: Diet, High-Fat, Endocrinology, lcsh:Biology (General), chemistry, MESH: Endotoxemia, MESH : Animals, Insulin Resistance, MESH: Disease Models, Animal, MESH: Lipopolysaccharides, Adipocyte hypertrophy
Abstract

International audience; Adipose tissue fibrosis development blocks adipocyte hypertrophy and favors ectopic lipid accumulation. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in humans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte metabolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll-like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a functional Toll-like receptor 4 on adipose tissue hematopoietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low-dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, promotes adipose tissue fibrosis. Ex vivo, lipopolysaccharide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFβ1. Together, these results indicate that obesity and endotoxemia favor the development of adipose tissue fibrosis, a condition associated with insulin resistance, through immune cell Toll-like receptor 4.

Published
2014

11. Pro-fibrotic activity of lysophosphatidic acid in adipose tissue: In vivo and in vitro evidence

Author

Jean-Loup Bascands, Pauline Decaunes, Philippe Valet, Chloé Rancoule, Jean Sébastien Saulnier-Blache, Sandra Grès, Nathalie Viguerie, Manon Viaud, Anne Bouloumié, 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), Service de Biochimie, 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, 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, Mice, Obese, Adipose tissue, Tissue Culture Techniques, Mice, chemistry.chemical_compound, 0302 clinical medicine, Transforming Growth Factor beta, Fibrosis, MESH: Collagen, Lysophosphatidic acid, MESH: Receptors, Lysophosphatidic Acid, MESH: Animals, MESH: Propionates, Receptors, Lysophosphatidic Acid, Receptor, MESH: Mice, Obese, 0303 health sciences, MESH: Indazoles, Adipose Tissue, 030220 oncology & carcinogenesis, MESH: Fibrosis, Female, lipids (amino acids, peptides, and proteins), Collagen, Autotaxin, MESH: Adipose Tissue, medicine.medical_specialty, Indazoles, Enzyme Activators, Biology, MESH: Actins, MESH: Hypoxia-Inducible Factor 1, alpha Subunit, MESH: Lysophospholipids, 03 medical and health sciences, In vivo, Internal medicine, medicine, Animals, Humans, MESH: Enzyme Activators, MESH: Tissue Culture Techniques, MESH: Mice, Molecular Biology, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Humans, Isoxazoles, Cell Biology, Hypoxia-Inducible Factor 1, alpha Subunit, medicine.disease, Actins, MESH: Male, In vitro, CTGF, Endocrinology, MESH: Isoxazoles, chemistry, Lysophospholipids, Propionates, MESH: Female
Abstract

International audience; Lysophosphatidic acid (LPA) is a pro-fibrotic mediator acting via specific receptors (LPARs) and is synthesized by autotaxin, that increases with obesity. We tested whether LPA could play a role in adipose tissue (AT)-fibrosis associated with obesity. Fibrosis [type I, III, and IV collagens (COL), fibronectin (FN), TGFβ, CTGF and αSMA] and inflammation (MCP1 and F4/80) markers were quantified: (i) in vivo in inguinal (IAT) and perigonadic (PGAT) AT from obese-diabetic db/db mice treated with the LPAR antagonist Ki16425 (5mg/kg/day ip for 7 weeks); and (ii) in vitro in human AT explants in primary culture for 72h in the presence of oleoyl-LPA (10μM) and/or Ki16425 (10μM) and/or the HIF-1α inhibitor YC-1 (100μM). Treatment of db/db mice with Ki16425 reduced Col I and IV mRNAs in IAT and PGAT while Col III mRNAs were only reduced in IAT. This was associated with reduction of COL protein staining in both IAT and PGAT. AT explants showed a spontaneous and time-dependent increase in ATX expression and production of LPA in the culture medium, along with increased levels of Col I and III, TGFβ and αSMA mRNAs and of COL protein staining. In vitro fibrosis was blocked by Ki16425 and was further amplified by oleoyl-LPA. LPA-dependent in vitro fibrosis was blocked by co-treatment with YC1. Our results show that endogenous and exogenous LPA exert a pro-fibrotic activity in AT in vivo and in vitro. This activity could be mediated by an LPA1R-dependent pathway and could involve HIF-1α.

Published
2014

12. Elastin-derived peptides potentiate atherosclerosis through the immune Neu1–PI3Kγ pathway

Author

Matthias P. Wymann, Laurent Debelle, Audrey Castaing-Berthou, Sébastien Blaise, Aurélie Montheil, Pascal Maurice, Roselyne Garnotel, Stéphanie Gayral, Alexey V. Pshezhetsky, Elodie Berge, Laurent O. Martinez, Laurent Duca, Nicole Malet, Laurent Martiny, Anne Fougerat, Muriel Laffargue, Departement /u563 : Lipoproteines et Mediateurs Lipidiques, Centre de Physiopathologie Toulouse Purpan (CPTP), 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)-Centre National de la Recherche Scientifique (CNRS)-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)-Centre National de la Recherche Scientifique (CNRS), Université de Reims Champagne-Ardenne (URCA), 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 de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Department of Biomedicine, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Division of Medical Genetics, CHU Sainte Justine [Montréal], Simon, Marie Francoise, Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Class I Phosphatidylinositol 3-Kinases, Physiology, [SDV]Life Sciences [q-bio], Neuraminidase, Receptors, Cell Surface, Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cathepsin A, Monocytes, Phosphatidylinositol 3-Kinases, NEU1, In vivo, Physiology (medical), medicine, Animals, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cathepsin, Atherosclerosis, medicine.disease, Elastin, 3. Good health, Cell biology, Mice, Inbred C57BL, Atheroma, Receptors, LDL, Biochemistry, biology.protein, Diet, Atherogenic, medicine.symptom, Peptides, Cardiology and Cardiovascular Medicine, Signal Transduction
Abstract

International audience; AIMS: Elastin is degraded during vascular ageing and its products, elastin-derived peptides (EP), are present in the human blood circulation. EP binds to the elastin receptor complex (ERC) at the cell surface, composed of elastin-binding protein (EBP), a cathepsin A and a neuraminidase 1. Some in vitro functions have clearly been attributed to this binding, but the in vivo implications for arterial diseases have never been clearly investigated. METHODS AND RESULTS: Here, we demonstrate that chronic doses of EP injected into mouse models of atherosclerosis increase atherosclerotic plaque size formation. Similar effects were observed following an injection of a VGVAPG peptide, suggesting that the ERC mediates these effects. The absence of phosphoinositide 3-kinase γ (PI3Kγ) in bone marrow-derived cells prevented EP-induced atherosclerosis development, demonstrating that PI3Kγ drive EP-induced arterial lesions. Accordingly, in vitro studies showed that PI3Kγ was required for EP-induced monocyte migration and ROS production and that this effect was dependent upon neuraminidase activity. Finally, we showed that degradation of elastic lamellae in LDLR(-/-) mice fed an atherogenic diet correlated with atherosclerotic plaque formation. At the same time, the absence of the cathepsin A-neuraminidase 1 complex in cells of the haematopoietic lineage abolished atheroma plaque size progression and decreased leucocytes infiltration, clearly demonstrating the role of this complex in atherogenesis and suggesting the involvement of endogenous EP. CONCLUSION: Altogether, this work identifies EP as an enhancer of atherogenesis and defines the Neuraminidase 1/PI3Kγ signalling pathway as a key mediator of this function in vitro and in vivo.

Published
2013

13. Transcatheter Aortic Valve Implantation Reduces Sympathetic Activity and Normalizes Arterial Spontaneous Baroreflex in Patients With Aortic Stenosis

Author

Atul Pathak, Didier Carrié, Nicolas Dumonteil, Bertrand Marcheix, Jean-Michel Senard, Angelica Vaccaro, Michel Galinier, Elisabeth Lambert, Murray D. Esler, Fabien Despas, Marc Labrunee, Service de cardiologie [Toulouse], Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], 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), 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), Service de Pharmacologie Clinique, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital Purpan [Toulouse], Human Neurotransmitter Laboratory, Baker IDI Heart and Diabetes Institute, Service Cardiologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (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), Service Pharmacologie Clinique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], and Simon, Marie Francoise

Subjects
Male, Cardiac Catheterization, medicine.medical_specialty, Sympathetic nervous system, Sympathetic Nervous System, Time Factors, Transcatheter aortic, Blood Pressure, 030204 cardiovascular system & hematology, Baroreflex, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Heart Rate, Internal medicine, Humans, Medicine, In patient, Prospective Studies, 030212 general & internal medicine, Muscle, Skeletal, transcatheter aortic valve implantation, Aged, Aged, 80 and over, Heart Valve Prosthesis Implantation, 2. Zero hunger, business.industry, Arterial baroreflex, aortic stenosis, arterial baroreflex, Aortic Valve Stenosis, medicine.disease, Stenosis, Treatment Outcome, Blood pressure, medicine.anatomical_structure, Case-Control Studies, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Body mass index
Abstract

International audience; OBJECTIVES: This study sought to measure muscle sympathetic nerve activity (MSNA) in patients with aortic stenosis (AS) before and after transcatheter aortic valve implantation (TAVI) and to compare MSNA with that of control patients. BACKGROUND: TAVI is an emerging therapeutic option in patients with severe AS at high risk of open heart surgery. Whether patients with AS have increased sympathetic activity remains to be established, and the effects of TAVI on the sympathetic nervous system are also unknown. METHODS: We prospectively enrolled 14 patients with severe symptomatic AS treated by TAVI. Fourteen control patients matched for age, body mass index, and unscathed of AS were also included. All patients underwent MSNA and arterial baroreflex gain assessment at baseline and 1 week after TAVI for AS patients. RESULTS: Patients with AS had lower blood pressure (BP) levels, a significant increase in MSNA (61.0 ± 1.7 burst/min vs. 55.4 ± 1.4 burst/min; p < 0.05), and a decrease in arterial baroreflex gain (2.13 ± 0.14% burst/mm Hg vs. 3.32 ± 0.19% burst/mm Hg; p < 0.01) compared with matched control patients. The TAVI procedures induced an increase in BP associated with a significant decrease in MSNA (from 61.0 ± 1.7 burst/min to 54.1 ± 1.0 burst/min; p < 0.01) and was associated with a significant increase in arterial baroreflex gain (from 2.13 ± 0.14% burst/mm Hg to 3.49 ± 0.33% burst/mm Hg; p < 0.01). CONCLUSIONS: We report for the first time, through direct measurement of nerve activity, that patients with AS have increased sympathetic nervous system activity associated with a decrease in sympathetic baroreflex gain and that TAVI normalizes these parameters. This study provides evidence of a new beneficial effect of TAVI, namely, normalization of sympathetic nervous system hyperactivity.

Published
2013

14. Cardiorenal anemia syndrome in chronic heart failure contributes to increased sympathetic nerve activity

Author

Nicolas Franchitto, Jean-Michel Senard, Angelica Vaccaro, Gavin W. Lambert, Atul Pathak, Elisabeth Lambert, Fabien Despas, Marc Labrunee, Michel Galinier, Service de médecine légale, Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service de Pharmacologie Clinique, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], 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), Service de cardiologie [Toulouse], Human Neurotransmitter Laboratory, Baker IDI Heart and Diabetes Institute, Service Médecine légale et médecine pénitentiaire [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Pharmacologie Clinique [CHU Toulouse], Service Cardiologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], and Simon, Marie Francoise

Subjects
Male, medicine.medical_specialty, Sympathetic Nervous System, Cardiomyopathy, Hemodynamics, Blood Pressure, 030204 cardiovascular system & hematology, Baroreflex, Ventricular Function, Left, Electrocardiography, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Double-Blind Method, Internal medicine, medicine, Humans, Prospective Studies, cardiovascular diseases, 030212 general & internal medicine, Aged, Heart Failure, Ejection fraction, Cardio-Renal Syndrome, business.industry, Anemia, Microneurography, Middle Aged, Prognosis, medicine.disease, Chemoreceptor Cells, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Blood pressure, Heart failure, Anesthesia, Disease Progression, cardiovascular system, Cardiology, Reflex, Female, Cardiology and Cardiovascular Medicine, business, human activities, Follow-Up Studies, circulatory and respiratory physiology
Abstract

International audience; BACKGROUND: We sought to assess whether cardiorenal anemia syndrome (CRAS) in chronic heart failure (CHF) patients contributes to sympathetic overactivity through modulation of sympathetic reflexes. METHODS AND RESULTS: We prospectively studied 15 patients with CRAS and CHF and 15 control CHF patients, matched for age, gender distribution, type of cardiomyopathy, left ventricular ejection fraction (LVEF) and BMI. We compared muscle sympathetic nerve activity (MSNA) and the effect of peripheral chemoreflex deactivation on MSNA in both groups. We also compared sympathetic baroreflex function, assessed by the slope of the relationship between MSNA and diastolic blood pressure in both groups and while peripheral chemoreflexes were (by breathing 100% oxygen for 15min) or not deactivated. Baseline MSNA was significantly elevated in CHF patients with CRAS compared with control CHF patients (83.1±4.6 versus 64.9±2.9bursts/100 heart beats; P

Published
2013

15. Epac in cardiac calcium signaling

Author

Anna Llach, Jean-Pierre Benitah, Alejandro Domínguez-Rodríguez, Frank Lezoualc'h, Eric Morel, Gema Ruiz-Hurtado, Ana María Gómez, Signalisation et physiopathologie cardiaque, Université Paris-Sud - Paris 11 (UP11)-IFR141-Institut National de la Santé et de la Recherche Médicale (INSERM), Unidad de Hipertensión, Hospital 12 de Octubre-Instituto de Investigación imas12, 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
Mef2, medicine.medical_specialty, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 030204 cardiovascular system & hematology, MESH: Calcium Signaling, MESH: Ryanodine Receptor Calcium Release Channel, 03 medical and health sciences, 0302 clinical medicine, Stress, Physiological, MESH: Excitation Contraction Coupling, Internal medicine, Ca2+/calmodulin-dependent protein kinase, Cyclic AMP, medicine, Animals, Guanine Nucleotide Exchange Factors, Humans, MESH: Guanine Nucleotide Exchange Factors, Myocyte, MESH: Animals, Calcium Signaling, MESH: Stress, Physiological, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Excitation Contraction Coupling, MESH: Cyclic AMP, 030304 developmental biology, Calcium signaling, 0303 health sciences, MESH: Humans, Phospholipase C, Chemistry, Ryanodine receptor, Endoplasmic reticulum, Ryanodine Receptor Calcium Release Channel, Cell biology, Sarcoplasmic Reticulum, Endocrinology, Type C Phospholipases, MESH: Calcium, MESH: Calcium-Calmodulin-Dependent Protein Kinase Type 2, MESH: Sarcoplasmic Reticulum, Phosphorylation, Calcium, MESH: Type C Phospholipases, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cardiology and Cardiovascular Medicine
Abstract

Epac, exchange protein directly activated by cAMP, is emerging as a new regulator of cardiac physiopathology. Although its effects are much less known than the classical cAMP effector, PKA, several studies have investigated the cardiac role of Epac, providing evidences that Epac modulates intracellular Ca 2 + . In one of the first analyses, it was shown that Epac can increase the frequency of spontaneous Ca 2 + oscillations in cultured rat cardiomyocytes. Later on, in adult cardiomyocytes, it was shown that Epac can induce sarcoplasmic reticulum (SR) Ca 2 + release in a PKA independent manner. The pathway identified involved phospholipase C (PLC) and Ca 2 + /calmodulin kinase II (CaMKII). The latter phosphorylates the ryanodine receptor (RyR), increasing the Ca 2 + spark probability. The RyR, Ca 2 + release channel located in the SR membrane, is a key element in the excitation–contraction coupling. Thus Epac participates in the excitation–contraction coupling. Moreover, by inducing RyR phosphorylation, Epac is arrhythmogenic. A detailed analysis of Ca 2 + mobilization in different microdomains showed that Epac preferently elevated Ca 2 + in the nucleoplasm ([Ca 2 + ] n ). This effect, besides PLC and CaMKII, required inositol 1,4,5 trisphosphate receptor (IP 3 R) activation. IP 3 R is other Ca 2 + release channel located mainly in the perinuclear area in the adult ventricular myocytes, where it has been shown to participate in the excitation–transcription coupling (the process by which Ca 2 + activates transcription). If Epac activation is maintained for some time, the histone deacetylase (HDAC) is translocated out of the nucleus de-repressing the transcription factor myocyte enhancer factor (MEF2). These evidences also pointed to Epac role in activating the excitation–transcription coupling. In fact, it has been shown that Epac induces cardiomyocyte hypertrophy. Epac activation for several hours, even before the cell hypertrophies, induces a profound modulation of the excitation–contraction coupling: increasing the [Ca 2 + ] i transient amplitude and cellular contraction. Thus Epac actions are rapid but time and microdomain dependent in the cardiac myocyte. Taken together the results collected indicate that Epac may have an important role in the cardiac response to stress. This article is part of a Special Issue entitled "Calcium Signaling in Heart".

Published
2013

16. Specific interactions between Epac1, β-arrestin2 and PDE4D5 regulate β-adrenergic receptor subtype differential effects on cardiac hypertrophic signaling

Author

Alexandre Lucas, Aude Saulière, George S. Baillie, Anne-Coline Laurent, Céline Galés, Magali Berthouze-Duquesnes, Yuan Yan Sin, Frank Lezoualc'h, 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), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, and Simon, Marie Francoise

Subjects
MESH: Signal Transduction, Scaffold protein, MESH: Fluorescence Resonance Energy Transfer, Arrestins, MESH: Myocytes, Cardiac, 030204 cardiovascular system & hematology, 0302 clinical medicine, MESH: RNA, Small Interfering, Fluorescence Resonance Energy Transfer, Guanine Nucleotide Exchange Factors, MESH: Guanine Nucleotide Exchange Factors, Myocytes, Cardiac, MESH: Animals, Protein Interaction Maps, RNA, Small Interfering, Cells, Cultured, beta-Arrestins, MESH: Protein Interaction Maps, 0303 health sciences, Gene knockdown, Cardiac myocyte, Phosphodiesterase, Cell biology, Biochemistry, MESH: HEK293 Cells, RNA Interference, Rap1, MESH: Arrestins, MESH: Cyclic Nucleotide Phosphodiesterases, Type 3, Signal Transduction, MESH: Cells, Cultured, MESH: Rats, MESH: RNA Interference, Cardiomegaly, Small G Protein, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Proto-Oncogene Proteins p21(ras), MESH: Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Animals, Humans, Nuclear export signal, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, MESH: Humans, Cell Biology, HDAC4, Cyclic Nucleotide Phosphodiesterases, Type 3, Cyclic Nucleotide Phosphodiesterases, Type 4, Rats, HEK293 Cells, Receptors, Adrenergic, beta-2, MESH: Receptors, Adrenergic, beta-1, Receptors, Adrenergic, beta-1, MESH: Cardiomegaly, MESH: Receptors, Adrenergic, beta-2
Abstract

International audience; β1 and β2 adrenergic receptors (βARs) are highly homologous but fulfill distinct physiological and pathophysiological roles. Here we show that both βAR subtypes activate the cAMP-binding protein Epac1, but they differentially affect its signaling. The distinct effects of βARs on Epac1 downstream effectors, the small G proteins Rap1 and H-Ras, involve different modes of interaction of Epac1 with the scaffolding protein β-arrestin2 and the cAMP-specific phosphodiesterase (PDE) variant PDE4D5. We found that β-arrestin2 acts as a scaffold for Epac1 and is necessary for Epac1 coupling to H-Ras. Accordingly, knockdown of β-arrestin2 prevented Epac1-induced histone deacetylase 4 (HDAC4) nuclear export and cardiac myocyte hypertrophy upon β1AR activation. Moreover, Epac1 competed with PDE4D5 for interaction with β-arrestin2 following β2AR activation. Dissociation of the PDE4D5-β-arrestin2 complex allowed the recruitment of Epac1 to β2AR and induced a switch from β2AR non-hypertrophic signaling to a β1AR-like pro-hypertrophic signaling cascade. These findings have implications for understanding the molecular basis of cardiac myocyte remodeling and other cellular processes in which βAR subtypes exert opposing effects.

Published
2013

17. Role of serotonin 5-HT2A receptors in the development of cardiac hypertrophy in response to aortic constriction in mice

Author

Stéphane Schaak, Angelo Parini, Denis Calise, Olivier Lairez, T. Cognet, Céline Guilbeau-Frugier, Jeanne Mialet-Perez, 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), Modélisation de l'Agression Tissulaire et de la Nociception (MATN), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]

Subjects
Male, medicine.medical_specialty, medicine.drug_class, Receptor expression, Cardiomegaly, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Constriction, Pathologic, 030204 cardiovascular system & hematology, Biology, Histone Deacetylases, Muscle hypertrophy, Mice, 03 medical and health sciences, 0302 clinical medicine, Piperidines, Internal medicine, Ca2+/calmodulin-dependent protein kinase, medicine, Animals, Receptor, Serotonin, 5-HT2A, RNA, Messenger, Receptor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Aorta, Biological Psychiatry, 030304 developmental biology, Pressure overload, Analysis of Variance, 0303 health sciences, Myocardium, Age Factors, Hemodynamics, Receptor antagonist, Fluorobenzenes, Mice, Inbred C57BL, Disease Models, Animal, Psychiatry and Mental health, Endocrinology, Gene Expression Regulation, Neurology, Echocardiography, cardiovascular system, Serotonin Antagonists, Neurology (clinical), Serotonin, Signal transduction, Calcium-Calmodulin-Dependent Protein Kinase Type 2
Abstract

International audience; Serotonin, in addition to its fundamental role as a neurotransmitter, plays a critical role in the cardiovascular system, where it is thought to be involved in the development of cardiac hypertrophy and failure. Indeed, we recently found that mice with deletion of monoamine oxidase A had enhanced levels of blood and cardiac 5-HT, which contributed to exacerbation of hypertrophy in a model of experimental pressure overload. 5-HT2A receptors are expressed in the heart and mediate a hypertrophic response to 5-HT in cardiac cells. However, their role in cardiac remodeling in vivo and the signaling pathways associated are not well understood. In the present study, we evaluated the effect of a selective 5-HT2A receptor antagonist, M100907, on the development of cardiac hypertrophy induced by transverse aortic constriction (TAC). Cardiac 5-HT2A receptor expression was transiently increased after TAC, and was recapitulated in cardiomyocytes, as observed with 5-HT2A in situ labeling by immunohistochemistry. Selective blockade of 5-HT2A receptors prevented the development of cardiac hypertrophy, as measured by echocardiography, cardiomyocyte area and heart weight-to-body weight ratio. Interestingly, activation of calmodulin kinase (CamKII), which is a core mechanism in cardiac hypertrophy, was reduced in cardiac samples from M100907-treated TAC mice compared to vehicle-treated mice. In addition, phosphorylation of histone deacetylase 4 (HDAC4), a downstream partner of CamKII was significantly diminished in M100907-treated TAC mice. Thus, our results show that selective blockade of 5-HT2A receptors has beneficial effect in the development of cardiac hypertrophy through inhibition of the CamKII/HDAC4 pathway.

Published
2013

18. Analyses of single nucleotide polymorphisms in selected nutrient-sensitive genes in weight-regain prevention: the DIOGENES study

Author

Lesli H. Larsen, Marie Kunešová, Arne Astrup, Dominique Langin, Marleen A. van Baak, J. Alfredo Martínez, Susan A. Jebb, Wim H. M. Saris, Karani Santhanakrishnan Vimaleswaran, Andreas Pfeiffer, Claus Holst, Teodora Handjieva-Darlenska, Nathalie Viguerie, Angeliki Papadaki, Jorg Hager, Lars Ängquist, Thomas Larsen, Thorkild I. A. Sørensen, Ruth J. F. Loos, Department of Human Nutrition, Faculty of Life Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Institute of Preventive Medicine, Copenhagen University Hospitals, MRC Epidemiology Unit, Addenbrooke's Hospital-Institute of Metabolic Science, 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, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Metabolic Science, MRC, Department of Nutrition, Dietetics and Metabolic Diseases, National Transport Hospital, MRC Human Nutrition Research, Elsie Widdowson Laboratory, Institute of Endocrinology, Obesity Management Center, Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), Department of Social Medicine, University of Crete [Heraklion] (UOC), Department of Endocrinology, Diabetes & Nutrition, German Institute of Human Nutrition-Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism-Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht]-Maastricht University [Maastricht], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), 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), Simon, Marie Francoise, Humane Biologie, and RS: NUTRIM - R1 - Metabolic Syndrome

Subjects
Male, 030309 nutrition & dietetics, BEHAVIOR INTERACTIONS, MESH: Dietary Proteins, PROTEIN, Medicine (miscellaneous), MESH: Food Habits, Weight Gain, Body Mass Index, MESH: Genotype, 0302 clinical medicine, Weight loss, MESH: Obesity, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, 0303 health sciences, Nutrition and Dietetics, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH: DNA, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Glycemic index, OBESITY, MESH: Waist Circumference, MESH: Weight Gain, DIETS, Female, Dietary Proteins, Waist Circumference, medicine.symptom, Adult, medicine.medical_specialty, Waist, Genotype, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, LOSS MAINTENANCE, Biology, Polymorphism, Single Nucleotide, MESH: Genetic Loci, MESH: Body Mass Index, 03 medical and health sciences, MESH: Weight Loss, Internal medicine, Weight Loss, medicine, Humans, Caloric Restriction, Glycemic, MESH: Caloric Restriction, MESH: Humans, MESH: Adult, DNA, Feeding Behavior, medicine.disease, Obesity, MESH: Male, Endocrinology, Genetic Loci, MESH: Glycemic Index, GLYCEMIC INDEX, Body mass index, Weight gain, MESH: Female
Abstract

International audience; BACKGROUND: Differences in the interindividual response to dietary intervention could be modified by genetic variation in nutrient-sensitive genes. OBJECTIVE: This study examined single nucleotide polymorphisms (SNPs) in presumed nutrient-sensitive candidate genes for obesity and obesity-related diseases for main and dietary interaction effects on weight, waist circumference, and fat mass regain over 6 mo. DESIGN: In total, 742 participants who had lost ≥ 8% of their initial body weight were randomly assigned to follow 1 of 5 different ad libitum diets with different glycemic indexes and contents of dietary protein. The SNP main and SNP-diet interaction effects were analyzed by using linear regression models, corrected for multiple testing by using Bonferroni correction and evaluated by using quantile-quantile (Q-Q) plots. RESULTS: After correction for multiple testing, none of the SNPs were significantly associated with weight, waist circumference, or fat mass regain. Q-Q plots showed that ALOX5AP rs4769873 showed a higher observed than predicted P value for the association with less waist circumference regain over 6 mo (-3.1 cm/allele; 95% CI: -4.6, -1.6; P/Bonferroni-corrected P = 0.000039/0.076), independently of diet. Additional associations were identified by using Q-Q plots for SNPs in ALOX5AP, TNF, and KCNJ11 for main effects; in LPL and TUB for glycemic index interaction effects on waist circumference regain; in GHRL, CCK, MLXIPL, and LEPR on weight; in PPARC1A, PCK2, ALOX5AP, PYY, and ADRB3 on waist circumference; and in PPARD, FABP1, PLAUR, and LPIN1 on fat mass regain for dietary protein interaction. CONCLUSION: The observed effects of SNP-diet interactions on weight, waist, and fat mass regain suggest that genetic variation in nutrient-sensitive genes can modify the response to diet. This trial was registered at clinicaltrials.gov as NCT00390637.

Published
2016

19. Intraparenchymal Injection of Bone Marrow Mesenchymal Stem Cells Reduces Kidney Fibrosis after Ischemia-Reperfusion in Cyclosporine-Immunosuppressed Rats

Author

Caroline Ceccaldi, Jean-Loup Bascands, Daniel Cussac, Angelo Parini, Céline Mias, Denis Calise, Chiara Alfarano, Christophe Roubeix, Rana Chaaya, 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 Saint-Joseph de Beyrouth (USJ), Centre interuniversitaire de recherche et d'ingenierie des matériaux (CIRIMAT), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, and Simon, Marie Francoise

Subjects
Adult, Male, Pathology, medicine.medical_specialty, 030232 urology & nephrology, Biomedical Engineering, Ischemia, lcsh:Medicine, Renal function, Bone Marrow Cells, Kidney, Mesenchymal Stem Cell Transplantation, 03 medical and health sciences, 0302 clinical medicine, Renal fibrosis, Animals, Humans, Medicine, Kidney transplantation, 030304 developmental biology, 0303 health sciences, Transplantation, business.industry, lcsh:R, Mesenchymal stem cell, Mesenchymal Stem Cells, Cell Biology, Middle Aged, [SDV.ETH] Life Sciences [q-bio]/Ethics, medicine.disease, Fibrosis, [SDV.ETH]Life Sciences [q-bio]/Ethics, Rats, 3. Good health, Disease Models, Animal, medicine.anatomical_structure, Rats, Inbred Lew, Reperfusion Injury, Immunology, Cyclosporine, Female, Kidney Diseases, Bone marrow, business, Cell activation, Immunosuppressive Agents
Abstract

International audience; Ischemia-reperfusion and immunosuppressive therapy are a major cause of progressive renal failure after kidney transplantation. Recent studies have shown that administration of bone marrow mesenchymal stem cells (MSCs) improves kidney functional recovery in the acute phase of post ischemia-reperfusion injury. In the present study, we used an original model of renal ischemia-reperfusion in immunosuppressed rats (NIRC) to investigate the effects of bone marrow MSCs on progression of chronic renal failure and the mechanisms potentially involved. Left renal ischemia-reperfusion (IR) was induced in unilateral nephrectomized Lewis rats. After IR, rats were treated daily with cyclosporine (10 mg/kg SC) for 28 days. MSCs were injected into the kidney at day 7 after IR. At day 28 after IR, kidneys were removed for histomorphological, biochemical, and gene expression analysis. The effect of conditioned media from MSCs on epithelial-mesenchymal transition was studied in vitro on HK2 cells. Our results show that, as compared to untreated NIRC rats, rats treated by intrarenal injection of MSCs 7 days after IR displayed improvement in renal function, reduction of interstitial fibrosis, and decrease in chronic tubule injury. These effects were associated with a decrease in interstitial α-SMA accumulation and MMP2 activity, markers of fibroblast/fibroblast-like cell activation, and renal remodeling, respectively. Finally, experiments in vitro showed that MSC-conditioned medium prevented epithelial-mesenchymal transition induced by TGF-β in HK2 cells. In conclusion, our results show that, in immunosuppressed animals, a single intrarenal administration of MSCs reduced renal fibrosis and promoted the recovery of renal function.

Published
2012

20. Chronic estradiol treatment reduces platelet responses and protects mice from thromboembolism through the hematopoietic estrogen receptor α

Author

Jean-François Arnal, Cendrine Cabou, Pierre Sié, Marie-Cécile Valéra, Pierre Gourdy, Françoise Lenfant, Bernard Payrastre, Nathalie Laurent, Marlène Marcellin, Michel Sixou, Marie-Pierre Gratacap, Céline E. Toutain, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, 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), Faculté des Sciences Pharmaceutiques, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Simon, Marie Francoise, Faculté de Chirurgie Dentaire, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Laboratoire d'Hématologie [Rangueil], Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, and CHU Toulouse [Toulouse]

Subjects
Blood Platelets, medicine.medical_specialty, Bleeding Time, Platelet Aggregation, Proteome, medicine.drug_class, Ovariectomy, Immunology, Estrogen receptor, 030204 cardiovascular system & hematology, Biology, Biochemistry, Mice, 03 medical and health sciences, 0302 clinical medicine, Tubulin, In vivo, Thromboembolism, Internal medicine, Antithrombotic, medicine, Animals, Platelet, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Estradiol, Estrogen Receptor alpha, Cell Biology, Hematology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Hematopoietic Stem Cells, medicine.disease, 3. Good health, Mice, Inbred C57BL, Atheroma, Endocrinology, Estrogen, Ovariectomized rat, Female, Gene Deletion, Ex vivo
Abstract

Although estrogens are known to have a deleterious effect on the venous thrombosis risk and a preventive action on the development of arterial atheroma, their effect on platelet function in vivo remains unclear. Here, we demonstrate that a chronic high physiologic level of estradiol (E2) in mice leads to a marked decrease in platelet responsiveness ex vivo and in vivo compared with ovariectomized controls. E2 treatment led to increased bleeding time and a resistance to thromboembolism. Hematopoietic chimera mice harboring a selective deletion of estrogen receptors (ERs) α or β were used to demonstrate that the effects of E2 were exclusively because of hematopoietic ERα. Within ERα the activation function-1 domain was not required for resistance to thromboembolism, as was previously shown for atheroprotection. This domain is mandatory for E2-mediated reproductive function and suggests that this role is controlled independently. Differential proteomics indicated that E2 treatment modulated the expression of platelet proteins including β1 tubulin and a few other proteins that may impact platelet production and activation. Overall, these data demonstrate a previously unrecognized role for E2 in regulating the platelet proteome and platelet function, and point to new potential antithrombotic and vasculoprotective therapeutic strategies.

Published
2012

21. Polymorphisms of protein tyrosine phosphatase CD148 influence FcγRIIA-dependent platelet activation and the risk of heparin-induced thrombocytopenia

Author

Michel Aupart, Bernard Payrastre, Yves Gruel, Valérie Gouilleux-Gruart, Dorothee Leroux, Jérôme Rollin, Marie-Pierre Gratacap, Marc-Antoine May, Claire Pouplard, Laboratoire d'Hématologie-Hémostase, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours (UT)-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), Service d'Anesthésie-Réanimation, Service de Chirurgie Cardiaque, Laboratoire d'Immunologie, Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Simon, Marie Francoise, Université de Tours-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Hématologie [Rangueil], Hôpital de Rangueil, and CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]

Subjects
Male, Genotype, Immunology, Linker for Activation of T cells, Protein tyrosine phosphatase, 030204 cardiovascular system & hematology, Biology, Platelet Factor 4, Polymorphism, Single Nucleotide, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Heparin-induced thrombocytopenia, medicine, Humans, Genetic Predisposition to Disease, Platelet, Platelet activation, 030304 developmental biology, 0303 health sciences, Heparin, Receptor-Like Protein Tyrosine Phosphatases, Class 3, Receptors, IgG, Cell Biology, Hematology, Platelet Activation, medicine.disease, Thrombocytopenia, Molecular biology, 3. Good health, Case-Control Studies, Phosphorylation, Female, Protein Tyrosine Phosphatases, Platelet factor 4, Proto-oncogene tyrosine-protein kinase Src
Abstract

Heparin-induced thrombocytopenia (HIT) is due primarily to IgG antibodies specific to platelet factor 4/heparin complexes (PF4/Hs) that activate platelets via FcγRIIA. CD148 is a protein tyrosine phosphatase that regulates Src kinases and collagen-induced platelet activation. Three polymorphisms affecting CD148 (Q276P, R326Q, and D872E) were studied in HIT patients and 2 control groups, with or without antibodies to PF4/Hs. Heterozygote status for CD148 276P or 326Q alleles was less frequent in HIT patients, suggesting a protective effect of these polymorphisms. Aggregation tests performed with collagen, HIT plasma, and monoclonal antibodies cross-linking FcγRIIA showed consistent hyporesponsiveness of platelets expressing the 276P/326Q alleles. In addition, platelets expressing the 276P/326Q alleles exhibited a greater sensitivity to the Src family kinases inhibitor dasatinib in response to collagen or ALB6 cross-linking FcγRIIA receptors. Moreover, the activatory phosphorylation of Src family kinases was considerably delayed as well as the phosphorylation of Linker for activation of T cells and phospholipase Cγ2, 2 major signaling proteins downstream from FcγRIIA. In conclusion, this study shows that CD148 polymorphisms affect platelet activation and probably exert a protec-tive effect on the risk of HIT in patients with antibodies to PF4/Hs.

Published
2012

22. Assessment of the Scopa-Aut questionnaire in multiple system atrophy: Relation to UMSARS scores and progression over time

Author

Jean-Michel Senard, Wassilios G. Meissner, Valérie Cochen De Cock, Angélique Gerdelat-Mas, Olivier Rascol, Rachel Debs, François Tison, Anne Pavy-Le Traon, Alexandra Foubert-Samier, Nathalie Damon-Perrière, Service de Neurologie, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Centre de référence de l’atrophie multisystématisée [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Pharmacologie Clinique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Centre de référence de l'atrophie multisystématisée [Bordeaux] (AMS), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), and Simon, Marie Francoise

Subjects
Male, medicine.medical_specialty, Autonomic failure, Urinary system, Dopamine Agents, Scopa, Severity of Illness Index, Cohort Studies, Disability Evaluation, Atrophy, Rating scale, Surveys and Questionnaires, Internal medicine, Severity of illness, medicine, Humans, Pure autonomic failure, Aged, Chi-Square Distribution, Follow-up, Middle Aged, Multiple System Atrophy, medicine.disease, Autonomic Nervous System Diseases, Atypical parkinsonism, Neurology, Physical therapy, Regression Analysis, Female, Neurology (clinical), Geriatrics and Gerontology, Psychology, Chi-squared distribution, Cohort study
Abstract

International audience; Autonomic failure is a key feature of multiple system atrophy (MSA). Moreover, early autonomic failure is an independent predictive factor for rapid disease progression and shorter survival. The assessment of autonomic failure is therefore important for both, the diagnosis and prognosis of MSA. Here, we evaluate autonomic dysfunction in MSA patients by the Scopa-Aut questionnaire. Potential associations between the Scopa-Aut questionnaire and established markers of disease progression - that is the Unified MSA Rating Scale (UMSARS) - were further assessed. The results confirm early and prominent autonomic failure in MSA patients. Relative scores were highest for the sexual and urinary subdomains. Surprisingly, relative scores in the cardiovascular subdomain were lowest suggesting that the Scopa-Aut questionnaire is suboptimal for the screening and evaluation of cardiovascular symptoms in MSA. A multivariate regression showed an association between total Scopa-Aut and UMSARS I scores. No significant changes in Scopa-Aut scores were observed during follow-up except for the urinary subdomain, while UMSARS I, II and IV scores significantly increased over time. In conclusion, Scopa-Aut can be used as a simple auto-questionnaire for the screening of autonomic symptoms in multiple system atrophy. It seems not useful as endpoint for disease-modification or neuroprotection trials.

Published
2012

23. Regulation of skeletal muscle lipolysis and oxidative metabolism by the co-lipase CGI-58

Author

Cedric Moro, Steven R. Smith, Camille Loubière, Aline Mairal, Dominique Langin, Virginie Bourlier, Pierre-Marie Badin, Katie Louche, Arild C. Rustan, Geneviève Tavernier, Maarten Coonen, 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 Pharmaceutical Biosciences, University of Oslo (UiO), Translational Research Institute for Metabolism and Diabetes and the Burnham Institute, Florida Hospital, and Simon, Marie Francoise

Subjects
MESH: Oxidation-Reduction, Hydrolases, Muscle Fibers, Skeletal, Peroxisome proliferator-activated receptor, Mitochondrion, Biochemistry, MESH: Lipase, Mice, 0302 clinical medicine, Endocrinology, substrate oxidation, MESH: Animals, PPAR delta, Research Articles, Cells, Cultured, chemistry.chemical_classification, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, MESH: Muscle, Skeletal, MESH: Muscle Fibers, Skeletal, Myogenesis, MESH: Gene Expression Regulation, Enzymologic, Fatty Acids, MESH: Energy Metabolism, 1-Acylglycerol-3-Phosphate O-Acyltransferase, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, humanities, MESH: Hydrolases, MESH: Fatty Acids, MESH: Glucose, mitochondria, medicine.anatomical_structure, MESH: Young Adult, Gene Knockdown Techniques, Peroxisome proliferator-activated receptor delta, Oxidation-Reduction, MESH: Cells, Cultured, MESH: Triglycerides, Adolescent, MESH: 1-Acylglycerol-3-Phosphate O-Acyltransferase, MESH: Mitochondria, Lipolysis, 030209 endocrinology & metabolism, Oxidative phosphorylation, QD415-436, Biology, Gene Expression Regulation, Enzymologic, Young Adult, 03 medical and health sciences, health services administration, mental disorders, medicine, Animals, Humans, MESH: Lipolysis, MESH: PPAR delta, Muscle, Skeletal, Glycogen synthase, MESH: Mice, Triglycerides, 030304 developmental biology, MESH: Adolescent, MESH: Humans, comparative gene identification 58, peroxisome proliferator-activated receptor, intramyocellular triacylglycerol, Skeletal muscle, Lipase, Cell Biology, MESH: Gene Knockdown Techniques, Glucose, chemistry, biology.protein, fatty acid, Energy Metabolism
Abstract

International audience; We investigated here the specific role of CGI-58 in the regulation of energy metabolism in skeletal muscle. We first examined CGI-58 protein expression in various muscle types in mice, and next modulated CGI-58 expression during overexpression and knockdown studies in human primary myotubes and evaluated the consequences on oxidative metabolism. We observed a preferential expression of CGI-58 in oxidative muscles in mice consistent with triacylglycerol hydrolase activity. We next showed by pulse-chase that CGI-58 overexpression increased by more than 2-fold the rate of triacylglycerol (TAG) hydrolysis, as well as TAG-derived fatty acid (FA) release and oxidation. Oppositely, CGI-58 silencing reduced TAG hydrolysis and TAG-derived FA release and oxidation (-77%, P < 0.001), whereas it increased glucose oxidation and glycogen synthesis. Interestingly, modulations of CGI-58 expression and FA release are reflected by changes in pyruvate dehydrogenase kinase 4 gene expression. This regulation involves the activation of the peroxisome proliferator activating receptor-δ (PPARδ) by lipolysis products. Altogether, these data reveal that CGI-58 plays a limiting role in the control of oxidative metabolism by modulating FA availability and the expression of PPARδ-target genes, and highlight an important metabolic function of CGI-58 in skeletal muscle.

Published
2012

24. Apelin, a promising target for type 2 diabetes treatment?

Author

Claude Knauf, Isabelle Castan-Laurell, Philippe Valet, Cédric Dray, Oxana Kunduzova, 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
medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Adipose tissue, 030209 endocrinology & metabolism, Type 2 diabetes, Biology, Models, Biological, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin resistance, Internal medicine, Small peptide, medicine, Humans, MESH: Intercellular Signaling Peptides and Proteins, 030304 developmental biology, 0303 health sciences, MESH: Humans, MESH: Models, Biological, Type 2 Diabetes Mellitus, Metabolism, medicine.disease, Obesity, Apelin, MESH: Insulin Resistance, Adipose Tissue, Diabetes Mellitus, Type 2, Intercellular Signaling Peptides and Proteins, Insulin Resistance, MESH: Adipose Tissue, MESH: Diabetes Mellitus, Type 2
Abstract

International audience; Insulin resistance is a main feature of obesity and type 2 diabetes mellitus (T2DM). Several mechanisms linking obesity to insulin resistance have been proposed. Adipose tissue modulates metabolism by secreting a variety of factors, which exhibit altered production during obesity. Apelin, a small peptide present in a number of tissues and also produced and secreted by adipocytes, has emerged as a new player with potent functions in energy metabolism, and in insulin sensitivity improvement. In this review, we describe the various metabolic functions that are affected by apelin and we present an integrated overview of recent findings that collectively propose apelin as a promising target for the treatment of T2DM.

Published
2012

25. Ephrin-B1 Is a Novel Specific Component of the Lateral Membrane of the Cardiomyocyte and Is Essential for the Stability of Cardiac Tissue Architecture Cohesion

Author

Christophe Heymes, Michael D. Schneider, Céline Galés, Benjamin Honton, Denis Calise, Alexandre Dubrac, Christelle Coatrieux, Alice Davy, Etienne Dague, Christelle Cardin, Jean-Michel Senard, Marie-Hélène Seguelas, Fabien Despas, Bruno Payré, Marie-Bernadette Delisle, Céline Guilbeau-Frugier, Dina N. Arvanitis, Gael Genet, Caroline Dubroca, Pauline Marck, Marie-Françoise Altié, Atul Pathak, Cécile Nieto, 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), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut des Technologies Avancées en sciences du Vivant (ITAV), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), National Heart and Lung Institute, Imperial College London-British Heart Foundation, Centre de Microscopie Électronique Appliquée à la Biologie (CMEAB), Toulouse Réseau Imagerie-Genotoul ( TRI-Genotoul), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de biologie du développement (CBD), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service Pharmacologie Clinique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Simon, Marie Francoise, Service d'histopathologie, CHU Toulouse [Toulouse], Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Toulouse Réseau Imagerie-Genotoul ( TRI-Genotoul), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), and Laboratoire de pharmacologie médicale et clinique

Subjects
Male, Physiology, MESH: Myocytes, Cardiac, Cell Communication, Matrix (biology), MESH: Mice, Knockout, Extracellular matrix, Mice, MESH: Collagen, Myocyte, Myocytes, Cardiac, MESH: Animals, Cells, Cultured, Ultrasonography, Mice, Knockout, 0303 health sciences, MESH: Sarcomeres, 030302 biochemistry & molecular biology, Anatomy, Cell biology, medicine.anatomical_structure, MESH: Models, Animal, Models, Animal, Collagen, MESH: Endothelium, Vascular, MESH: Membrane Proteins, Cardiology and Cardiovascular Medicine, MESH: Cells, Cultured, Sarcomeres, animal structures, Ephrin-B1, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Cell Communication, Dystroglycan, medicine, Animals, Ephrin, MESH: Mice, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Pressure overload, Basement membrane, MESH: Ephrin-B1, Cell Membrane, Erythropoietin-producing hepatocellular (Eph) receptor, Membrane Proteins, MESH: Male, Mice, Inbred C57BL, biology.protein, Endothelium, Vascular, sense organs, MESH: Cell Membrane
Abstract

Rationale: Cardiac tissue cohesion relying on highly ordered cardiomyocytes (CM) interactions is critical because most cardiomyopathies are associated with tissue remodeling and architecture alterations. Objective: Eph/ephrin system constitutes a ubiquitous system coordinating cellular communications which recently emerged as a major regulator in adult organs. We examined if eph/ephrin could participate in cardiac tissue cyto-organization. Methods and Results: We reported the expression of cardiac ephrin-B1 in both endothelial cells and for the first time in CMs where ephrin-B1 localized specifically at the lateral membrane. Ephrin-B1 knock-out (KO) mice progressively developed cardiac tissue disorganization with loss of adult CM rod-shape and sarcomeric and intercalated disk structural disorganization confirmed in CM-specific ephrin-B1 KO mice. CMs lateral membrane exhibited abnormal structure by electron microscopy and notably increased stiffness by atomic force microscopy. In wild-type CMs, ephrin-B1 interacted with claudin-5/ZO-1 complex at the lateral membrane, whereas the complex disappeared in KO/CM-specific ephrin-B1 KO mice. Ephrin-B1 deficiency resulted in decreased mRNA expression of CM basement membrane components and disorganized fibrillar collagen matrix, independently of classical integrin/dystroglycan system. KO/CM-specific ephrin-B1 KO mice exhibited increased left ventricle diameter and delayed atrioventricular conduction. Under pressure overload stress, KO mice were prone to death and exhibited striking tissue disorganization. Finally, failing CMs displayed downregulated ephrin-B1/claudin-5 gene expression linearly related to the ejection fraction. Conclusions: Ephrin-B1 is necessary for cardiac tissue architecture cohesion by stabilizing the adult CM morphology through regulation of its lateral membrane. Because decreased ephrin-B1 is associated with molecular/functional cardiac defects, it could represent a new actor in the transition toward heart failure.

Published
2012

26. Urinary Proteome Analysis at 5-Year Followup of Patients With Nonoperated Ureteropelvic Junction Obstruction Suggests Ongoing Kidney Remodeling

Author

Stéphane Decramer, Justyna Siwy, Joost P. Schanstra, Harald Mischak, Benjamin Breuil, Flavio Bandin, Jean-Loup Bascands, Service de Pédiatrie - Néphrologie, Médecine interne, Hypertension, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Référence du sud-Ouest des maladies rénales rares [CHU Toulouse] (SODARE), 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), Protein Analysis for Clinical Diagnosis and Pharmaceutical Research, Mosaiques Diagnostics and Therapeutics AG, British Heart Foundation - Glasgow Cardiovascular Research Center, (BHF - GCRC), University of Glasgow-Institute of Cardiovascular and Medical Sciences-Faculty of Medical, Veterinary and Life Sciences, Simon, Marie Francoise, CHU Toulouse [Toulouse]-Hôpital des Enfants, CHU Toulouse [Toulouse], Centre de Référence du sud-Ouest des maladies rénales rares, and CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]

Subjects
Male, MESH: Electrophoresis, Capillary, Proteome, medicine.medical_treatment, 030232 urology & nephrology, Kidney, Kidney Function Tests, urologic and male genital diseases, Mass Spectrometry, 0302 clinical medicine, MESH: Child, Medicine, Child, MESH: Statistics, Nonparametric, 0303 health sciences, MESH: Case-Control Studies, MESH: Watchful Waiting, 3. Good health, MESH: Proteome, medicine.anatomical_structure, MESH: Kidney Function Tests, Child, Preschool, Female, Ureteral Obstruction, medicine.medical_specialty, Urology, Urinary system, Renal function, Statistics, Nonparametric, 03 medical and health sciences, Humans, Watchful Waiting, Hydronephrosis, Retrospective Studies, 030304 developmental biology, MESH: Mass Spectrometry, MESH: Humans, business.industry, MESH: Child, Preschool, MESH: Biological Markers, Case-control study, Electrophoresis, Capillary, MESH: Retrospective Studies, Retrospective cohort study, MESH: Kidney, medicine.disease, MESH: Male, Surgery, Case-Control Studies, MESH: Ureteral Obstruction, business, MESH: Female, Biomarkers, Watchful waiting
Abstract

International audience; PURPOSE: Severe ureteropelvic junction obstruction is treated surgically. However, for milder cases most clinical teams adopt a watchful waiting approach and only operate in the presence of significant decline of renal function combined with severe hydronephrosis. Little is known about the long-term consequences of ureteropelvic junction obstruction. MATERIALS AND METHODS: Using capillary electrophoresis coupled with mass spectrometry, we analyzed the urinary proteome of 42 patients with ureteropelvic junction obstruction 5 years postoperatively or 5 years following spontaneous resolution. RESULTS: At 5-year followup urinary proteomes were similar between patients with early surgical correction of ureteropelvic junction obstruction and age matched controls. In contrast, urinary proteomes differed significantly between conservatively followed patients and controls. Analyses of the proteomic differences suggested ongoing renal or ureteral remodeling in the conservatively followed patients that was not visible clinically. CONCLUSIONS: Long-term followup studies are warranted in patients with ureteropelvic junction obstruction, especially those followed conservatively, to determine whether the observed changes in the urinary proteomes become clinically relevant at a later stage.

Published
2012

27. Host-Gut Microbiota Metabolic Interactions

Author

Rémy Burcelin, Sven Pettersson, Elaine Holmes, Glenn R. Gibson, Jeremy K. Nicholson, James Kinross, Wei Jia, Simon, Marie Francoise, Biomolecular Medicine, Imperial College London, 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 Food and Nutritional Sciences, University of Reading (UOR), Department of Nutrition, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Department of Microbiology, Tumor, and Cell Biology (MTC), Karolinska Institutet [Stockholm], and School of Biological Sciences and National Cancer Centre

Subjects
MESH: Signal Transduction, MESH: Inflammation, Aging, Host genome, MESH: Health, Gut–brain axis, Microbial metabolism, MESH: Metabolic Diseases, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Gut flora, digestive system, 03 medical and health sciences, 0302 clinical medicine, Metabolic Diseases, MESH: Diet, Animals, Humans, MESH: Aging, MESH: Animals, 030304 developmental biology, Inflammation, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, MESH: Humans, MESH: Immune System, Bacteria, Extramural, Host (biology), MESH: Metagenome, biology.organism_classification, Diet, Cell biology, Gastrointestinal Tract, Metabolic pathway, MESH: Bacteria, Liver metabolism, Liver, Health, MESH: Metabolic Networks and Pathways, Immune System, Immunology, Metagenome, MESH: Gastrointestinal Tract, Metabolic Networks and Pathways, 030217 neurology & neurosurgery, Signal Transduction, MESH: Liver
Abstract

International audience; The composition and activity of the gut microbiota codevelop with the host from birth and is subject to a complex interplay that depends on the host genome, nutrition, and life-style. The gut microbiota is involved in the regulation of multiple host metabolic pathways, giving rise to interactive host-microbiota metabolic, signaling, and immune-inflammatory axes that physiologically connect the gut, liver, muscle, and brain. A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to manipulate the gut microbiota to combat disease and improve health.

Published
2012
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28. The gut microbiota profile is associated with insulin action in humans

Author

Alex Sánchez, Maribel Queipo-Ortuño, José María Moreno-Navarrete, José Manuel Fernández-Real, Rémy Burcelin, Francisco J. Tinahones, Eduardo García Fuentes, Matteo Serino, 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 Diabetes Endocrinology and Nutrition, Instituto de Salud Carlos III [Madrid] (ISC)-CIBER Fisiopatologia Obesidad y Nutricion, Service of Endocrinology and Nutrition, CIBER Fisiopatologia Obesidad y Nutricion-Universitario Virgen de Victoria de Malaga, Statistics Department, University of Barcelona, Institut de Recerca, Vall d'Hebron University Hospital [Barcelona], This work was partially supported by research grants from the Ministerio de Educacio'n y Ciencia (SAF2008-0273) to JMFR, from the Agence Nationale de la Recherche (ANR FLORADIP and FLORINFLAM) to RB, and from Socie'te' Francophone du Diabe'te-Glaxo Smith Kline (SFD-GSK) and the Benjamin Delessert foundation both to MS. Alex Sanchez is supported by the Ministerio de Educacio'n y Ciencia-MTM2008-0064., and Simon, Marie Francoise

Subjects
Male, Microbial DNA, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV.GEN] Life Sciences [q-bio]/Genetics, Gut flora, Transcriptome, 0302 clinical medicine, Endocrinology, MESH: Obesity, Insulin, DGGE, DNA, Fungal, 2. Zero hunger, Genetics, 0303 health sciences, MESH: Middle Aged, Microbiota, General Medicine, Middle Aged, MESH: Case-Control Studies, 3. Good health, MESH: Insulin Resistance, Female, Original Article, Adult, DNA, Bacterial, 030209 endocrinology & metabolism, MESH: Insulin, Gut microbiota, Biology, Quantitative trait locus, Diet, High-Fat, digestive system, 03 medical and health sciences, Insulin resistance, Internal Medicine, medicine, MESH: Microbiota, Humans, Obesity, 030304 developmental biology, Insulin action, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Microarray analysis techniques, MESH: Transcriptome, MESH: Adult, Metabolic diseases, MESH: Metagenome, medicine.disease, biology.organism_classification, Microarray Analysis, MESH: DNA, Bacterial, MESH: Male, MESH: DNA, Fungal, Gastrointestinal Tract, MESH: Microarray Analysis, MESH: Diet, High-Fat, Metagenomics, Case-Control Studies, Metagenome, MESH: Gastrointestinal Tract, Insulin Resistance, MESH: Female
Abstract

International audience; The role of the gut microbiota in the induction of metabolic diseases has now been increasingly recognized worldwide. Indeed, a specific gut microbiota has been shown to characterize lean versus obese phenotypes both in humans and mice. We have also recently demonstrated that a precise gut microbiota is associated with the host's responsiveness to a high-fat diet. Therefore, we hypothesized that insulin resistance in humans could also be linked to a specific gut microbiota. To this aim, microbial DNA and RNA were extracted from the appendix contents of insulin-resistant versus insulin-sensitive obese subjects, matched for body mass index and age, and analyzed by DNA- and RNA-DGGE. Microbial DNA analysis showed that the patients fully segregated according to their degree of insulin action. Conversely, microbial RNA investigation showed that some degree of homology still existed between insulin-sensitive and insulin-resistant patients. Quantitative trait analysis, ordinary least squares regression, principal components regression, partial least squares, canonical correlation analysis, and canonical correspondence analysis also showed a net separation of the two phenotypes analyzed. We conclude that a specific gut microbial profile is associated with insulin action in humans.

Published
2012
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29. Circulating ACE is a predictor of weight loss maintenance not only in overweight and obese women, but also in men

Author

Wang, P., Holst, C., Wodzig, W. K. W. H., Andersen, M. R., Astrup, A., Van Baak, M. A., Larsen, T. M., Jebb, S. A., Kafatos, A., Pfeiffer, A. F. H., Martinez, J. A., Handjieva-Darlenska, T., Kunesova, M., Viguerie, N., Langin, D., Saris, W. H. M., Mariman, E. C. M., Diogenes, Consortium, Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism-Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht]-Maastricht University [Maastricht], Institute of Preventive Medicine / Institut for Sygdomsforebyggelse, Copenhagen University Hospital-Frederiksberg Hospital Hovedvejen, Department of Clinical Chemistry, Maastricht University Medical Centre (MUMC), Department of Clinical Biochemistry, Copenhagen University Hospital, Department of Human Nutrition, Faculty of Life Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Elsie Widdowson Laboratory, MRC Human Nutrition Research, Department of Social Medicine, Preventive Medicine and Nutrition Clinic, University of Crete [Heraklion] (UOC), Department of Clinical Nutrition, German Institute of Human Nutrition, Department of Endocrinology, Diabetes and Nutrition, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), Department of Nutrition, Dietetics and Metabolic Diseases, National Multiprofile Transport Hospital, Obesity Management Centre, Institute of Endocrinology, Obesity Research Laboratory, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Department of Human Biology Nutrition and Toxicology Research (Diogenes), Maastricht University [Maastricht]-Institute Maastricht (NUTRIM), Humane Biologie, MUMC+: DA CDL Algemeen (9), RS: NUTRIM - R4 - Gene-environment interaction, RS: NUTRIM - R1 - Metabolic Syndrome, Simon, Marie Francoise, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Cross-sectional study, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), MESH: Energy Intake, 030204 cardiovascular system & hematology, Overweight, Weight Gain, 0302 clinical medicine, Weight loss, MESH: Obesity, 2. Zero hunger, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Diet, Reducing, 0303 health sciences, Nutrition and Dietetics, MESH: Middle Aged, MESH: Sex Distribution, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Predictive Value of Tests, 3. Good health, MESH: Weight Gain, Female, medicine.symptom, Adult, medicine.medical_specialty, Diet, Reducing, Peptidyl-Dipeptidase A, 03 medical and health sciences, MESH: Weight Loss, MESH: Cross-Sectional Studies, Predictive Value of Tests, Internal medicine, Weight Loss, medicine, Humans, Obesity, Sex Distribution, 030304 developmental biology, MESH: Humans, business.industry, MESH: Biological Markers, MESH: Adult, Odds ratio, Anthropometry, Confidence interval, MESH: Male, MESH: Peptidyl-Dipeptidase A, Endocrinology, Cross-Sectional Studies, business, Energy Intake, Weight gain, Body mass index, MESH: Female, Biomarkers
Abstract

BACKGROUND:Circulating angiotensin-converting enzyme (ACE) was identified as a predictor of weight loss maintenance in overweight/obese women of the Diogenes project.OBJECTIVE:To investigate whether ACE acted also as a predictor in men of the Diogenes study and to compare it with that in women.DESIGN:Subjects, who lost >/=8% of body weight induced by low-caloric diet in an 8-week weight loss period, were assigned to weight loss maintenance with dietary intervention for 6 months.SUBJECTS:125 overweight/obese healthy men from eight European countries who completed whole intervention.MEASUREMENTS:Concentrations and activity of serum ACE at baseline and after the 8-week weight loss, in addition to anthropometric and physiological parameters.RESULTS:Serum ACE concentration decreased by 11.3+/-10.6% during the weight loss period in men. A greater reduction is associated with less body weight regain during the maintenance period (r=0.227, P=0.012). ACE change was able to predict a weight regain

Published
2012

30. Key role of PI3K? in monocyte chemotactic protein-1-mediated amplification of PDGF-induced aortic smooth muscle cell migration

Author

Fougerat, Anne, Smirnova, Natalia, Gayral, Stéphanie, Malet, Nicole, Hirsch, Emilio, Wymann, Matthias, Perret, Bertrand, Martinez, Laurent, Douillon, Monique, Laffargue, Muriel, 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 Genetics, Biology and Biochemistry, Université de Turin, Institute of Biochemistry and Genetics, and Simon, Marie Francoise

Subjects
Receptors, CCR2, Swine, MESH: Mice, Transgenic, MESH: Aorta, Thoracic, MESH: Class Ib Phosphatidylinositol 3-Kinase, Myocytes, Smooth Muscle, Aorta, Thoracic, Mice, Transgenic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Recombinant Proteins, Mice, Cell Movement, MESH: Mice, Inbred C57BL, MESH: Receptors, CCR2, Animals, Class Ib Phosphatidylinositol 3-Kinase, MESH: Animals, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Swine, MESH: Cell Movement, MESH: Chemokine CCL2, MESH: Mice, Cells, Cultured, Chemokine CCL2, Platelet-Derived Growth Factor, MESH: Proto-Oncogene Proteins c-akt, MESH: Platelet-Derived Growth Factor, MESH: Myocytes, Smooth Muscle, Research Papers, Recombinant Proteins, Mice, Inbred C57BL, cardiovascular system, Proto-Oncogene Proteins c-akt, MESH: Cells, Cultured
Abstract

International audience; BACKGROUND AND PURPOSE: Vascular smooth muscle cell (SMC) migration within the arterial wall is a crucial event in atherogenesis and restenosis. Monocyte chemotactic protein-1/CC-chemokine receptor 2 (MCP-1/CCR2) signalling is involved in SMC migration processes but the molecular mechanisms have not been well characterized. We investigated the role of PI3Kγ in SMC migration induced by MCP-1. EXPERIMENTAL APPROACHES: A pharmacological PI3Kγ inhibitor, adenovirus encoding inactive forms of PI3Kγ and genetic deletion of PI3Kγ were used to investigate PI3Kγ functions in the MCP-1 and platelet-derived growth factor (PDGF) signalling pathway and migration process in primary aortic SMC. KEY RESULTS: The γ isoform of PI3K was shown to be the major signalling molecule mediating PKB phosphorylation in MCP-1-stimulated SMC. Using a PI3Kγ inhibitor and an adenovirus encoding a dominant negative form of PI3Kγ, we demonstrated that PI3Kγ is essential for SMC migration triggered by MCP-1. PDGF receptor stimulation induced MCP-1 mRNA and protein accumulation in SMCs. Blockade of the MCP-1/CCR2 pathway or pharmacological inhibition of PI3Kγ reduced PDGF-stimulated aortic SMC migration by 50%. Thus PDGF promotes an autocrine loop involving MCP-1/CCR2 signalling which is required for PDGF-mediated SMC migration. Furthermore, SMCs isolated from PI3Kγ-deficient mice (PI3Kγ(-/-)), or mice expressing an inactive PI3Kγ (PI3Kγ(KD/KD)), migrated less than control cells in response to MCP-1 and PDGF. CONCLUSIONS AND IMPLICATIONS: PI3Kγ is essential for MCP-1-stimulated aortic SMC migration and amplifies cell migration induced by PDGF by an autocrine/paracrine loop involving MCP-1 secretion and CCR2 activation. PI3Kγ is a promising target for the treatment of aortic fibroproliferative pathologies.

Published
2012
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31. Gut microbiota and diabetes: from pathogenesis to therapeutic perspective

Author

Vincent Blasco-Baque, Matteo Serino, Rémy Burcelin, Chantal Chabo, Jacques Amar, 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), Médecine Interne et Hypertension Artérielle [Rangueil], CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Simon, Marie Francoise, Service d'hypertension artérielle et thérapeutique [CHU Toulouse] (HTA et thérapeutique), Pôle Cardiovasculaire et Métabolique [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
MESH: Diabetes Mellitus, Endocrinology, Diabetes and Metabolism, Adipose tissue, 030209 endocrinology & metabolism, Inflammation, Review Article, Disease, Gut flora, Bioinformatics, Microbiology, 03 medical and health sciences, Diabetes mellitus genetics, 0302 clinical medicine, Endocrinology, Insulin resistance, Immune system, Diabetes Mellitus, Internal Medicine, medicine, Genetic predisposition, Animals, Humans, High throughput sequencing, MESH: Animals, Obesity, 030304 developmental biology, 0303 health sciences, MESH: Humans, Bacteria, biology, Type 2 diabetes, General Medicine, Prebiotic and probiotic, MESH: Metagenome, biology.organism_classification, medicine.disease, 3. Good health, Gastrointestinal Tract, MESH: Bacteria, Gut microbiota dysbiosis, Metagenome, MESH: Gastrointestinal Tract, medicine.symptom
Abstract

International audience; More than several hundreds of millions of people will be diabetic and obese over the next decades in front of which the actual therapeutic approaches aim at treating the consequences rather than causes of the impaired metabolism. This strategy is not efficient and new paradigms should be found. The wide analysis of the genome cannot predict or explain more than 10-20% of the disease, whereas changes in feeding and social behavior have certainly a major impact. However, the molecular mechanisms linking environmental factors and genetic susceptibility were so far not envisioned until the recent discovery of a hidden source of genomic diversity, i.e., the metagenome. More than 3 million genes from several hundreds of species constitute our intestinal microbiome. First key experiments have demonstrated that this biome can by itself transfer metabolic disease. The mechanisms are unknown but could be involved in the modulation of energy harvesting capacity by the host as well as the low-grade inflammation and the corresponding immune response on adipose tissue plasticity, hepatic steatosis, insulin resistance and even the secondary cardiovascular events. Secreted bacterial factors reach the circulating blood, and even full bacteria from intestinal microbiota can reach tissues where inflammation is triggered. The last 5 years have demonstrated that intestinal microbiota, at its molecular level, is a causal factor early in the development of the diseases. Nonetheless, much more need to be uncovered in order to identify first, new predictive biomarkers so that preventive strategies based on pre- and probiotics, and second, new therapeutic strategies against the cause rather than the consequence of hyperglycemia and body weight gain.

Published
2011

32. Central Apelin Controls Glucose Homeostasisviaa Nitric Oxide-Dependent Pathway in Mice

Author

Sophie Rastrelli, André Colom, Bernard Frances, Isabelle Castan-Laurell, Nathalie M. Delzenne, Isabelle Leclercq, Philippe Valet, Patrice D. Cani, Thibaut Duparc, Lionel Moulédous, Claude Knauf, Nicolas Massaly, J. Andrew Pospisilik, Catherine Llorens-Cortes, Sophie Le Gonidec, Anne Drougard, 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), Metabolism and nutrition research group, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Louvain Drug Research Institute (LDRI), Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), 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)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratory of hepato-gastroenterology, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Institut de Recherche Experimentale et Clinique, Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of immunobiology, Max-Planck-Institut, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches sur la Cognition Animale - UMR5169 (CRCA), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), 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)-Université Toulouse - Jean Jaurès (UT2J), 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)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, 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)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), 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)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)

Subjects
Physiology, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Adipose tissue, Biochemistry, Mice, chemistry.chemical_compound, 0302 clinical medicine, Insulin Secretion, Hyperinsulinemia, Homeostasis, Insulin, Glucose homeostasis, General Environmental Science, Neurons, 0303 health sciences, Brain, Circadian Rhythm, 3. Good health, Apelin, [SDV] Life Sciences [q-bio], Infusions, Intraventricular, Intercellular Signaling Peptides and Proteins, medicine.medical_specialty, Hypothalamus, 030209 endocrinology & metabolism, Carbohydrate metabolism, Nitric Oxide, Diabetes Mellitus, Experimental, Nitric oxide, 03 medical and health sciences, Insulin resistance, Adipokines, Internal medicine, medicine, Animals, Humans, Molecular Biology, 030304 developmental biology, business.industry, Cell Biology, medicine.disease, Biosynthetic Pathways, Glucose, Endocrinology, Diabetes Mellitus, Type 2, chemistry, General Earth and Planetary Sciences, Insulin Resistance, business
Abstract

International audience; Abstract Aims: Apelin and its receptor have emerged as promising targets for the treatment of insulin resistance. Indeed, peripheral administration of apelin stimulates glucose utilization and insulin sensitivity via a nitric oxide (NO) pathway. In addition to being expressed on peripheral metabolically active adipose tissues, apelin is also found in the brain. However, no data are available on the role of central effects of apelin on metabolic control. We studied glucose metabolism in response to acute and chronic intracerebroventricular (i.c.v.) injection of apelin performed in normal and obese/diabetic mice. Results: We demonstrate that i.c.v. injection of apelin into fed mice improves glucose control via NO-dependent mechanisms. These results have been strengthened by transgenic (eNOS-KO mice), pharmacological (L-NMMA i.c.v. treated mice), and real-time measurement of NO release with amperometric probes detection. High-fat diet-fed mice displayed a severely blunted response to i.c.v. apelin associated with a lack of NO response by the hypothalamus. Moreover, central administration of high dose apelin in fasted normal mice provoked hyperinsulinemia, hyperglycemia, glucose intolerance, and insulin resistance. Conclusion: These data provide compelling evidence that central apelin participates in the regulation of glucose homeostasis and suggest a novel pathophysiological mechanism involved in the transition from normal to diabetic state. Antioxid. Redox Signal. 15, 1477-1496.

Published
2011

33. Physiological and Pharmacological Mechanisms through which the DPP-4 Inhibitor Sitagliptin Regulates Glycemia in Mice

Author

Pierre Cattan, Julien Castel, Rémy Burcelin, Aurélie Waget, Daniel J. Drucker, Mattieu Armanet, Melis Karaca, Christophe Magnan, Jens J. Holst, Céline Garret, Thierry Sulpice, Gaëlle Payros, Myriam Masseboeuf, Adriano Maida, Cendrine Cabou, 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, Cell Therapy Unit, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], 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 ), Biologie Fonctionnelle et Adaptative ( BFA ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Medicine, University of Toronto-Samuel Lunenfeld Research Institute-Mount Sinai Hospital ( MSH ), Physiogenex SAS, Prologue Biotech, PHYSIOGENEX S.A.S, Department of Biomedical Sciences, The panum Institute-University of Copenhagen ( KU ), Institut des Maladies Métaboliques et Cardiovasculaires (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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Toronto-Samuel Lunenfeld Research Institute-Mount Sinai Hospital [Toronto, Canada] (MSH), Physiogenex, Department of Biomedical Sciences [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), University of Toronto-Mount Sinai Hospital [Toronto, Canada] (MSH)-Samuel Lunenfeld Research Institute, and University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)

Subjects
MESH : Insulin, medicine.medical_treatment, MESH : Vagus Nerve, MESH : Receptors, Glucagon, 0302 clinical medicine, Endocrinology, MESH: Dipeptides, MESH: Vagus Nerve, Glucose homeostasis, MESH: Animals, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH : Dipeptidyl-Peptidase IV Inhibitors, 0303 health sciences, Glucose tolerance test, MESH: Middle Aged, MESH: Dipeptidyl-Peptidase IV Inhibitors, medicine.diagnostic_test, MESH : Glucagon, MESH: Glucagon, digestive, oral, and skin physiology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH : Adult, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Glucagon-like peptide-1, 3. Good health, MESH : Pyrazines, MESH: Pyrazines, Sitagliptin, hormones, hormone substitutes, and hormone antagonists, medicine.drug, endocrine system, medicine.medical_specialty, MESH: Glucose Tolerance Test, MESH : Male, MESH : Dipeptides, MESH : Receptors, Gastrointestinal Hormone, Incretin, 030209 endocrinology & metabolism, MESH: Insulin, MESH : Mice, Inbred C57BL, Biology, Sitagliptin Phosphate, MESH : Glucose Tolerance Test, MESH: Receptors, Glucagon, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Internal medicine, MESH : Mice, MESH : Triazoles, medicine, MESH : Middle Aged, MESH: Mice, Dipeptidyl peptidase-4, 030304 developmental biology, MESH: Humans, MESH: Receptors, Gastrointestinal Hormone, Insulin, MESH : Humans, MESH: Adult, MESH: Dipeptidyl Peptidase 4, MESH : Blood Glucose, MESH: Male, MESH: Triazoles, MESH : Dipeptidyl Peptidase 4, MESH: Blood Glucose, MESH : Animals
Abstract

International audience; Inhibition of dipeptidyl peptidase-4 (DPP-4) activity improves glucose homeostasis through a mode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expressed on the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemic DPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestine. Glp1r(-/-) and Gipr(-/-) mice were studied and glucagon-like peptide (GLP)-1 receptor (GLP-1R) signaling was blocked by an i.v. infusion of the corresponding receptor antagonist exendin (9-39). The role of the dipeptides His-Ala and Tyr-Ala as DPP-4-generated GLP-1 and glucose-dependent insulinotropic peptide (GIP) degradation products was studied in vivo and in vitro on isolated islets. We demonstrate that very low doses of oral sitagliptin improve glucose tolerance and plasma insulin levels with selective reduction of intestinal but not systemic DPP-4 activity. The glucoregulatory action of sitagliptin was associated with increased vagus nerve activity and was diminished in wild-type mice treated with the GLP-1R antagonist exendin (9-39) and in Glp1r(-/-) and Gipr(-/-) mice. Furthermore, the dipeptides liberated from GLP-1 (His-Ala) and GIP (Tyr-Ala) deteriorated glucose tolerance, reduced insulin, and increased portal glucagon levels. The predominant mechanism through which DPP-4 inhibitors regulate glycemia involves local inhibition of intestinal DPP-4 activity, activation of incretin receptors, reduced liberation of bioactive dipeptides, and activation of the gut-to-pancreas neural axis.

Published
2011

34. New Perspectives in cAMP-Signaling Modulation

Author

Magali Berthouze, Anne-Coline Laurent, Frank Lezoualc'h, Magali Breckler, 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 Paris-Sud - Paris 11 (UP11), and Simon, Marie Francoise

Subjects
MESH: Signal Transduction, Scaffold protein, Phosphodiesterase 3, MESH: Receptors, Adrenergic, beta, MESH: Receptors, CCR10, MESH: Myocytes, Cardiac, MESH: Cyclic AMP-Dependent Protein Kinases, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Receptors, CCR10, 030204 cardiovascular system & hematology, Biology, Second Messenger Systems, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Receptors, Adrenergic, beta, Cyclic AMP, MESH: Guanine Nucleotide Exchange Factors, Guanine Nucleotide Exchange Factors, Humans, Myocytes, Cardiac, Protein kinase A, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Cyclic AMP, 030304 developmental biology, G protein-coupled receptor, Heart Failure, 0303 health sciences, MESH: Humans, Phosphoric Diester Hydrolases, Phosphodiesterase, Compartmentalization (psychology), Cyclic AMP-Dependent Protein Kinases, MESH: Second Messenger Systems, Cell biology, MESH: Heart Failure, Second messenger system, Emergency Medicine, PDE10A, Cardiology and Cardiovascular Medicine, MESH: Phosphoric Diester Hydrolases, Signal Transduction
Abstract

International audience; Cyclic adenosine 3',5'-monophosphate (cAMP) mediates the biological effects of various hormones and neurotransmitters. Stimulation of cardiac β-adrenergic receptors (β-AR) via catecholamines leads to activation of adenylyl cyclases and increases cAMP production to enhance myocardial function. Because many other receptors signaling through cAMP generation exist in cardiac myocytes, a central question is how different hormones induce distinct cellular responses through the same second messenger. A large body of evidence suggests that the localization and compartmentalization of β-AR/cAMP signaling affects the net outcome of biological functions. Spatiotemporal dynamics of cAMP action is achieved by various proteins, including protein kinase A (PKA), phosphodiesterases, and scaffolding proteins such as A-kinase-anchoring proteins. In addition, the discovery of the cAMP target Epac (exchange proteins directly activated by cAMP), which functions in a PKA-independent manner, represents a novel mechanism for governing cAMP-signaling specificity. Aberrant cAMP signaling through dysregulation of β-AR/cAMP compartmentalization may contribute to cardiac remodeling and heart failure.

Published
2011

35. Altered Skeletal Muscle Lipase Expression and Activity Contribute to Insulin Resistance in Humans

Author

Gerd Schmitz, Cedric Moro, Steven R. Smith, Gerhard Liebisch, Arild C. Rustan, Aline Mairal, Pierre-Marie Badin, Katie Louche, 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), Université Fédérale Toulouse Midi-Pyrénées, Institute of Clinical Chemistry, Universität Regensburg (UR), Department of Pharmaceutical Biosciences, University of Oslo (UiO), Translational Research Institute for Metabolism and Diabetes and the Burnham Institute, Florida 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], This work was supported by grants from the National Research Agency (ANR-09-JCJC-0019-01) and the European Foundation for the Study of Diabetes/Novo Nordisk (to C.M.), the Commission of the European Communities (Integrated Project HEPADIP, and National Institutes of Health grants US-1P30-DK-072476 (Pennington Biomedical Research Center/Nutrition Obesity Research Center) and R01-AG-030226 (to S.R.S.). The Hormone Assay and Analytical Services Core, Vanderbilt Diabetes Research and Training Center, supported by National Institutes of Health Grant DK-20593, performed TAG and DAG analyses., European Project: 32591,HEPADIP, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), 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, and Hepatic and adipose tissue and functions in the metabolic syndrome - HEPADIP - 32591 - OLD

Subjects
Male, Endocrinology, Diabetes and Metabolism, MESH: Glucose Clamp Technique, Mass Spectrometry, MESH: Lipase, 0302 clinical medicine, Tandem Mass Spectrometry, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, education.field_of_study, MESH: Muscle, Skeletal, MESH: Middle Aged, MESH: Sterol Esterase, biology, MESH: Chromatography, Gas, Glucose clamp technique, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, MESH: Insulin Resistance, medicine.anatomical_structure, MESH: Young Adult, lipids (amino acids, peptides, and proteins), Female, MESH: Triglycerides, Adult, medicine.medical_specialty, Spectrometry, Mass, Electrospray Ionization, Chromatography, Gas, Population, 030209 endocrinology & metabolism, MESH: Spectrometry, Mass, Electrospray Ionization, Pathophysiology, MESH: Diglycerides, Diglycerides, 03 medical and health sciences, Young Adult, Insulin resistance, Internal medicine, Internal Medicine, medicine, Humans, Glycogen synthase, education, Muscle, Skeletal, Protein kinase B, Triglycerides, 030304 developmental biology, MESH: Mass Spectrometry, MESH: Humans, Skeletal muscle, MESH: Tandem Mass Spectrometry, MESH: Adult, Lipase, Sterol Esterase, medicine.disease, MESH: Male, Insulin receptor, Endocrinology, Adipose triglyceride lipase, biology.protein, Glucose Clamp Technique, Insulin Resistance, MESH: Female
Abstract

OBJECTIVE Insulin resistance is associated with elevated content of skeletal muscle lipids, including triacylglycerols (TAGs) and diacylglycerols (DAGs). DAGs are by-products of lipolysis consecutive to TAG hydrolysis by adipose triglyceride lipase (ATGL) and are subsequently hydrolyzed by hormone-sensitive lipase (HSL). We hypothesized that an imbalance of ATGL relative to HSL (expression or activity) may contribute to DAG accumulation and insulin resistance. RESEARCH DESIGN AND METHODS We first measured lipase expression in vastus lateralis biopsies of young lean (n = 9), young obese (n = 9), and obese-matched type 2 diabetic (n = 8) subjects. We next investigated in vitro in human primary myotubes the impact of altered lipase expression/activity on lipid content and insulin signaling. RESULTS Muscle ATGL protein was negatively associated with whole-body insulin sensitivity in our population (r = −0.55, P = 0.005), whereas muscle HSL protein was reduced in obese subjects. We next showed that adenovirus-mediated ATGL overexpression in human primary myotubes induced DAG and ceramide accumulation. ATGL overexpression reduced insulin-stimulated glycogen synthesis (−30%, P < 0.05) and disrupted insulin signaling at Ser1101 of the insulin receptor substrate-1 and downstream Akt activation at Ser473. These defects were fully rescued by nonselective protein kinase C inhibition or concomitant HSL overexpression to restore a proper lipolytic balance. We show that selective HSL inhibition induces DAG accumulation and insulin resistance. CONCLUSIONS Altogether, the data indicate that altered ATGL and HSL expression in skeletal muscle could promote DAG accumulation and disrupt insulin signaling and action. Targeting skeletal muscle lipases may constitute an interesting strategy to improve insulin sensitivity in obesity and type 2 diabetes.

Published
2011

36. Cancer-Associated Adipocytes Exhibit an Activated Phenotype and Contribute to Breast Cancer Invasion

Author

Sophie Le Gonidec, Ignacio Garrido, Danièle Daviaud, Yuan Yuan Wang, Béatrice Dirat, Philippe Valet, Ghislaine Escourrou, Catherine Muller, Bernard Salles, Marta Dabek, Ludivine Bochet, Bilal Majed, Stéphanie Dauvillier, Aline Meulle, 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 pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Département de Biostatistiques, Institut Curie [Paris], Service de Chirurgie Oncologique, Institut Claudius Regaud, Service d'Anatomo-Pathologie et Histologie-Cytologie d'Histomorphologie [Rangueil], CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Dirat, Béatrice, Bochet, Ludivine, Dabek, Marta-Ewa, Daviaud, Danièle, Dauvilier, Stéphanie, Majed, Bilal, WANG, Yuan Yuan, Meulle, Aline, Salles, Bernard, Le Gonidec, Sophie, Garrido, Ignacio, Escourrou, Ghislaine, Valet, Philippe, and Muller, Catherine

Subjects
Cancer Research, [SDV]Life Sciences [q-bio], Adipose tissue, Mice, chemistry.chemical_compound, 0302 clinical medicine, Adipocyte, Adipocytes, MESH: Animals, Neoplasm Metastasis, 0303 health sciences, Interleukin, Phenotype, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, Female, medicine.medical_specialty, MESH: Cell Line, Tumor, MESH: Mammary Neoplasms, Experimental, Breast Neoplasms, Biology, MESH: Phenotype, Proinflammatory cytokine, MESH: Coculture Techniques, 03 medical and health sciences, Cell Line, Tumor, Internal medicine, medicine, Animals, Humans, Neoplasm Invasiveness, MESH: Mice, MESH: Adipocytes, 030304 developmental biology, MESH: Humans, Interleukin-6, Mammary Neoplasms, Experimental, Cancer, MESH: Neoplasm Invasiveness, medicine.disease, MESH: Neoplasm Metastasis, MESH: Interleukin-6, Coculture Techniques, Endocrinology, chemistry, Tumor progression, Cancer cell, Cancer research, MESH: Female, MESH: Breast Neoplasms
Abstract

Early local tumor invasion in breast cancer results in a likely encounter between cancer cells and mature adipocytes, but the role of these fat cells in tumor progression remains unclear. We show that murine and human tumor cells cocultivated with mature adipocytes exhibit increased invasive capacities in vitro and in vivo, using an original two-dimensional coculture system. Likewise, adipocytes cultivated with cancer cells also exhibit an altered phenotype in terms of delipidation and decreased adipocyte markers associated with the occurrence of an activated state characterized by overexpression of proteases, including matrix metalloproteinase-11, and proinflammatory cytokines [interleukin (IL)-6, IL-1β]. In the case of IL-6, we show that it plays a key role in the acquired proinvasive effect by tumor cells. Equally important, we confirm the presence of these modified adipocytes in human breast tumors by immunohistochemistry and quantitative PCR. Interestingly, the tumors of larger size and/or with lymph nodes involvement exhibit the higher levels of IL-6 in tumor surrounding adipocytes. Collectively, all our data provide in vitro and in vivo evidence that (i) invasive cancer cells dramatically impact surrounding adipocytes; (ii) peritumoral adipocytes exhibit a modified phenotype and specific biological features sufficient to be named cancer-associated adipocytes (CAA); and (iii) CAAs modify the cancer cell characteristics/phenotype leading to a more aggressive behavior. Our results strongly support the innovative concept that adipocytes participate in a highly complex vicious cycle orchestrated by cancer cells to promote tumor progression that might be amplified in obese patients. Cancer Res; 71(7); 2455–65. ©2011 AACR.

Published
2011

37. Expression and secretion of the novel adipokine tartrate-resistant acid phosphatase from adipose tissues of obese and lean women

Author

C Bambace, Göran N. Andersson, Jonas Andersson, Pernilla Lång, Tommy Olsson, Peter Arner, A Zakaroff-Girard, Johan W. E. Jocken, A Bouloumié, Kerstin Wåhlén, Division of Pathology, Karolinska Institutet [Stockholm]-University Hospital Huddinge, TEAM1 AVENIR, 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)-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), Department of Medicine, Karolinska Institutet [Stockholm]-Karolinska University Hospital Huddinge, Department of Public Health and Clinical Medicine, Umeå University, and Simon, Marie Francoise

Subjects
Male, Endocrinology, Diabetes and Metabolism, Mice, Obese, Medicine (miscellaneous), Adipose tissue, MESH: Flow Cytometry, White adipose tissue, Mice, chemistry.chemical_compound, Adipocyte, MESH: Obesity, MESH: Animals, MESH: Mice, Obese, Tartrate-resistant acid phosphatase, MESH: Aged, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Middle Aged, Nutrition and Dietetics, Chemistry, MESH: Enzyme-Linked Immunosorbent Assay, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Flow Cytometry, Isoenzymes, MESH: Insulin Resistance, MESH: Isoenzymes, Adult, medicine.medical_specialty, Adipose tissue macrophages, Acid Phosphatase, Subcutaneous Fat, Adipokine, Enzyme-Linked Immunosorbent Assay, MESH: Acid Phosphatase, MESH: Adipokines, MESH: Subcutaneous Fat, Adipokines, Thinness, In vivo, MESH: Analysis of Variance, Internal medicine, medicine, Animals, Humans, Secretion, Obesity, RNA, Messenger, MESH: Mice, Aged, MESH: RNA, Messenger, Analysis of Variance, MESH: Humans, MESH: Thinness, Interleukin-6, Tartrate-Resistant Acid Phosphatase, Tumor Necrosis Factor-alpha, Macrophages, Body Weight, MESH: Biological Markers, MESH: Macrophages, MESH: Adult, MESH: Interleukin-6, MESH: Male, MESH: Body Weight, Endocrinology, MESH: Tumor Necrosis Factor-alpha, Insulin Resistance, Biomarkers
Abstract

International audience; OBJECTIVE: Tartrate-resistant acid phosphatase (TRAP) expressed by adipose tissue macrophages (ATMs) induces mice obesity and human adipocyte differentiation in vitro. This study aimed to investigate whether TRAP was secreted differently from human obese versus lean adipose tissues and to identify the cellular source of adipose tissue TRAP. DESIGN: Subcutaneous adipose tissues obtained from healthy subjects. Enzyme-linked immunosorbent assays (ELISAs) for total (5a+5b) and cleaved TRAP (5b) were used. TRAP secretion was determined in adipose tissue biopsies, and mRNA expression was studied in cell types isolated from the same. SUBJECTS: Results of 24 lean and 24 obese women (in vitro) and 8 subjects (in vivo) were compared. The main outcome measurements were TRAP expression and secretion in vitro and in vivo. RESULTS: In-house total TRAP ELISA showed high sensitivity and a coefficient of variance of 11%. Adipose secretion of total TRAP was linear in vitro with time and was evident in vivo. Total TRAP secretion in vitro was similar in lean and obese women expressed per unit weight of the adipose tissue but correlated positively with the number/size of adipocytes (P ≤ 0.01) and with adipose secretion of tumor necrosis factor-α and interleukin-6 (P

Published
2011

38. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment

Author

Mathieu Bergé, Aurélie Waget, Philippe J. Sansonetti, Natalia F. Smirnova, Thierry Sulpice, Rémy Burcelin, Philippe Langella, Luis G. Bermúdez-Humarán, Nina Rautonen, Christelle Vachoux, Jacques Amar, Pascale Klopp, Chantal Chabo, Arthur C. Ouwehand, Sampo J. Lahtinen, Service d'hypertension artérielle et thérapeutique [CHU Toulouse] (HTA et thérapeutique), Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), 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), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Unité de recherche d'Écologie et Physiologie du Système Digestif (UEPSD), Institut National de la Recherche Agronomique (INRA), Laboratoire de microbiologie et génétique moléculaires - UMR5100 (LMGM), Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Adhésion Bacterienne et Formation de Biofilms, PRES Université de Toulouse, Physiogenex, DuPont Health & Nutrition, Pathogénie Microbienne Moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France - Chaire Microbiologie et Maladies infectieuses, Collège de France (CdF (institution)), Agence Nationale de la Recherche (ANR Floradip, Transflora, Vaiomer), European Commission [241913], Simon, Marie Francoise, 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-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-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 Médecine Interne et Hypertension Artérielle [Toulouse], CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], 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, Unité d'Ecologie et de Physiologie du Système Digestif, INRA, Unité d'écologie et de physiologie du système digestif, Laboratoire de microbiologie et génétique moléculaires (LMGM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Chaire Microbiologie et Maladies infectieuses

Subjects
Bifidobacterium lactis 420, obesity, MESH: Bifidobacterium, [SDV]Life Sciences [q-bio], Lipopolysaccharide Receptors, M CELLS, MESH: Nod1 Signaling Adaptor Protein, Adipose tissue, Chromosomal translocation, Bacteremia, INDUCED INFLAMMATION, Type 2 diabetes, MESH: Mice, Knockout, Bacterial Adhesion, law.invention, Probiotic, Mice, 0302 clinical medicine, law, Nod1 Signaling Adaptor Protein, IMMUNE-RESPONSE, MESH: Animals, Intestinal Mucosa, MESH: Bacteremia, pathogen-associated molecular pattern receptors, 2. Zero hunger, Mice, Knockout, 0303 health sciences, biology, diabetes, MESH: Escherichia coli, MESH: Antigens, CD14, GUT MICROBIOTA, 3. Good health, Bifidobacterium animalis, [SDV] Life Sciences [q-bio], ADIPOSE-TISSUE, Blood, Adipose Tissue, ESCHERICHIA-COLI, MESH: Intestinal Mucosa, inflammation, INDUCED INSULIN-RESISTANCE, HIGH-FAT-DIET, INNATE IMMUNITY, OBESE MICE, Molecular Medicine, medicine.symptom, MESH: Adipose Tissue, MESH: Bacterial Translocation, MESH: Diabetes Mellitus, Type 2, MESH: Myeloid Differentiation Factor 88, Research Article, CD14, 030209 endocrinology & metabolism, Inflammation, Diet, High-Fat, Microbiology, 03 medical and health sciences, Insulin resistance, MESH: Mice, Inbred C57BL, MESH: Blood, medicine, Escherichia coli, Animals, MESH: Bacterial Adhesion, MESH: Mice, 030304 developmental biology, Probiotics, medicine.disease, biology.organism_classification, Mice, Inbred C57BL, MESH: Diet, High-Fat, Diabetes Mellitus, Type 2, Bacterial Translocation, Immunology, Myeloid Differentiation Factor 88, Bifidobacterium, MESH: Probiotics
Abstract

International audience; A fat-enriched diet modifies intestinal microbiota and initiates a low-grade inflammation, insulin resistance and type-2 diabetes. Here, we demonstrate that before the onset of diabetes, after only one week of a high-fat diet (HFD), live commensal intestinal bacteria are present in large numbers in the adipose tissue and the blood where they can induce inflammation. This translocation is prevented in mice lacking the microbial pattern recognition receptors Nod1 or CD14, but overtly increased in Myd88 knockout and ob/ob mouse. This 'metabolic bacteremia' is characterized by an increased co-localization with dendritic cells from the intestinal lamina propria and by an augmented intestinal mucosal adherence of non-pathogenic Escherichia coli. The bacterial translocation process from intestine towards tissue can be reversed by six weeks of treatment with the probiotic strain Bifidobacterium animalis subsp. lactis 420, which improves the animals' overall inflammatory and metabolic status. Altogether, these data demonstrate that the early onset of HFD-induced hyperglycemia is characterized by an increased bacterial translocation from intestine towards tissues, fuelling a continuous metabolic bacteremia, which could represent new therapeutic targets.

Published
2011

39. GLP-1: What is known, new and controversial in 2010?

Author

Sylvie Dejager, Rémy Burcelin, 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), Recherche clinique et développement, Novartis Pharma SAS, and Novartis Pharma

Subjects
endocrine system, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Incretin, MESH: Insulin, Biology, Bioinformatics, Neuroprotection, MESH: Insulin-Secreting Cells, Endocrinology, Internal medicine, Diabetes mellitus, MESH: Molecular Targeted Therapy, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Internal Medicine, medicine, Endocrine system, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Endocrine System, MESH: Humans, MESH: Peptides, MESH: Glucagon, Insulin, digestive, oral, and skin physiology, MESH: Glucagon-Like Peptide 1, General Medicine, medicine.disease, Metformin, Beta cell, hormones, hormone substitutes, and hormone antagonists, Hormone, medicine.drug
Abstract

International audience; Over the past 2 years, more than 1300 manuscripts have been published on glucagon-like peptide-1 (GLP-1) and yet, what do we know about it for sure? The European Club for the Study of GLP-1 (EuCSGLP-1) has debated the latest controversies concerning GLP-1, including both fundamental and clinical aspects, and concluded that the control of glucose metabolism by GLP-1 requires paracrine activation of the enteric nervous system to regulate numerous physiological functions. This involves-but is not limited to-the endocrine pancreas, liver, cardiovascular system, gastric-emptying and the brain. For this reason, the role of GLP-1 as an endocrine hormone has come under question. As systemic concentration of the peptide was not thought to be relevant to its physiological action, it was proposed that dipeptidyl peptidase-4 (DPP4) inhibitors would involve the control of enteric, rather than circulating, DPP4 activity to effectively regulate glycaemia. In any case, the concomitant insulinotropic and glucagonostatic roles of GLP-1 were believed to be of equal importance to glucose control. Another important question was related to the role of GLP-1 on beta cell apoptosis, regeneration and differentiation in type 2 diabetic patients. Although evidence in vitro showed that GLP-1 controls these functions, such effects remain elusive in humans in vivo. Nevertheless, the consensus was that GLP-1 could control glucose responsiveness, one of the first impaired physiological functions at the onset of diabetes. The therapeutic efficiency of GLP-1 would be related to the initial restoration of glucose competence, while an increase of beta cell mass has not yet been demonstrated. From a clinical and fundamental point of view, it was concluded that, at the onset of diabetes, an initial triggering of GLP-1 secretion-by metformin coupled with a DPP4 inhibitor-would help to activate the gut-peripheral axis and, hence, restore adequate regulation of glycaemia. GLP-1 analogues would certainly be helpful in association with long-acting insulin (albeit off-label) in patients with impaired beta cells and GLP-1 secretory potential. However, a reliable and routine feasible test to systematically assess dynamic insulin secretion is essential. More important, factors that influence therapeutic response, such as compliance and lifestyle, as well as pharmacokinetics and dosing, disease duration, age, gender, ethnicity, patients' clinical characteristics, autonomic nervous system integrity and genotype characteristics also need to be considered. A few innovative perspectives have been debated, such as the recently discovered cardiovascular protective effects of the native GLP-1 peptide and its degradation product GLP-1(9-36), as well as the neuroprotection offered by GLP-1. Although still considered speculative, these perspectives remain hopeful and promising.

Published
2010

40. Functional divergence between 2 chemokines is conferred by single amino acid change

Author

Andreas Bikfalvi, Catherine Zanibellato, Cathy Quemener, Eric Lacazette, Wen-guey Wu, Frédéric Lopez, Alexandre Dubrac, Hervé Prats, Simon, Marie Francoise, Mécanismes moléculaires de l'angiogénèse, Université Bordeaux Segalen - Bordeaux 2-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- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Life Sciences, and Tsing Hua University

Subjects
Glycan, Molecular Sequence Data, Immunology, Dermatan Sulfate, Neovascularization, Physiologic, Plasma protein binding, Biology, Platelet Factor 4, Biochemistry, Cell Line, Glycosaminoglycan, Mice, chemistry.chemical_compound, In vivo, medicine, Animals, Humans, Amino Acid Sequence, Chondroitin sulfate, Amino Acids, Peptide sequence, Cell Proliferation, Mice, Inbred BALB C, Heparin, Cell Biology, Hematology, Heparan sulfate, Recombinant Proteins, chemistry, Mutation, biology.protein, Cattle, Heparitin Sulfate, Protein Binding, medicine.drug
Abstract

CXCL4 and CXCL4L1 are 2 closely related CXC chemokines that exhibit potent antiangiogenic activity. Because interactions with glycosaminoglycans play a crucial role in chemokines activity, we determined the binding parameters of CXCL4 and CXCL4L1 for heparin, heparan sulfate, and chondroitin sulfate B. We further demonstrated that the Leu67/His67 substitution is critical for the decrease in glycan binding of CXCL4L1 but also for the increase of its angiostatic activities. Using a set of mutants, we show that glycan affinity and angiostatic properties are not completely related. These data are reinforced using a monoclonal antibody that specifically recognizes structural modifications in CXCL4L1 due to the presence of His67 and that blocks its biologic activity. In vivo, half-life and diffusibility of CXCL4L1 compared with CXCL4 is strongly increased. As opposed to CXCL4L1, CXCL4 is preferentially retained at its site of expression. These findings establish that, despite small differences in the primary structure, CXCL4L1 is highly distinct from CXCL4. These observations are not only of great significance for the antiangiogenic activity of CXCL4L1 and for its potential use in clinical development but also for other biologic processes such as inflammation, thrombosis or tissue repair.

Published
2010

41. Characterization of Monoamine Oxidases in Mesenchymal Stem Cells: Role in Hydrogen Peroxide Generation and Serotonin-Dependent Apoptosis

Author

Angelo Parini, Céline Mias, Catherine Ordener, Marie-Hélène Seguelas, Elodie Trouche, Daniel Cussac, 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), and Université Fédérale Toulouse Midi-Pyrénées

Subjects
Imipramine, Cell, Apoptosis, 030204 cardiovascular system & hematology, 0302 clinical medicine, MESH: Oxidants, MESH: Animals, Sympathomimetics, MESH: Serotonin Plasma Membrane Transport Proteins, Cells, Cultured, MESH: Adrenergic Uptake Inhibitors, Serotonin transporter, bcl-2-Associated X Protein, Serotonin Plasma Membrane Transport Proteins, 0303 health sciences, Adrenergic Uptake Inhibitors, biology, MESH: Imipramine, Cytochromes c, MESH: Cytochromes c, Hematology, Oxidants, Cell biology, Isoenzymes, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, Biochemistry, MESH: Isoenzymes, MESH: Hydrogen Peroxide, MESH: Rats, Inbred Lew, Monoamine oxidase A, MESH: Tyramine, MESH: Cells, Cultured, medicine.drug, Serotonin, Monoamine Oxidase Inhibitors, MESH: Rats, MESH: Monoamine Oxidase Inhibitors, Tyramine, MESH: Pargyline, MESH: Monoamine Oxidase, 03 medical and health sciences, medicine, Animals, MESH: bcl-2-Associated X Protein, Monoamine Oxidase, 030304 developmental biology, MESH: Apoptosis, MESH: Sympathomimetics, Mesenchymal stem cell, Mesenchymal Stem Cells, Hydrogen Peroxide, Cell Biology, Pargyline, Rats, MESH: Mesenchymal Stem Cells, Monoamine neurotransmitter, MESH: Proto-Oncogene Proteins c-bcl-2, Rats, Inbred Lew, biology.protein, MESH: Serotonin, Developmental Biology
Abstract

International audience; Early death of grafted bone marrow mesenchymal stem cells (MSCs) represents a major limit to their use in cell therapy of solid organs. It is well known that oxidative stress plays a major role in cell death. We have recently shown that the serotonin-degrading enzyme monoamine oxidase A (MAO-A) generates large amount of hydrogen peroxide (H2O2) responsible for cell apoptosis. Hydrogen peroxide generation requires 5-HT internalization into the cell and its degradation by MAO-A. In the present study, we investigated whether MAO-A is expressed in MSCs and we defined its role in serotonin-dependent MSCs apoptosis. RT-PCR analysis and western blots showed that the serotonin transporter (SERT) and the 2 MAO isoenzymes, A and B, are expressed in MSCs. As shown by enzyme assays using [14C]serotonin or [14C]β-phenylethylamine as selective MAO-A or MAO-B substrates, MAO-A is largely predominant in MSCs. Incubation of MSCs with the MAO substrate tyramine led to a time-dependent generation of H2O2 that was prevented by the MAO inhibitor pargyline. Finally, exposure of the cells to serotonin promoted an increase in MSCs apoptosis prevented by pargyline and the SERT inhibitor imipramine. The pro-apoptotic effect of serotonin was associated to a decrease in the expression of the anti-apoptotic factor Bcl-2. In conclusion, these results show for the first time that the 5-HT-degrading enzyme MAO-A is an important source of H2O2 in MSCs and plays a major role in 5-HT-dependent MSCs apoptosis.

Published
2010

42. Lipid mobilization in subcutaneous adipose tissue during exercise in lean and obese humans. Roles of insulin and natriuretic peptides

Author

Vladimir Stich, François Crampes, Marie Adeline Marques, Michel Berlan, Dominique Larrouy, Jan Polak, Isabelle de Glisezinski, Katrien Koppo, Dominique Langin, Max Lafontan, Magda Bajzova, Jens Bülow, Johan Van de Voorde, Department of Sports Medicine, Charles University [Prague] (CU), Department of Pharmacology, Universiteit Gent = Ghent University [Belgium] (UGENT), 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), Franco-Czech Laboratory for Clinical Research on Obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Physiology, Bispebjerg 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], Service de médecine du sport, Simon, Marie Francoise, Universiteit Gent = Ghent University (UGENT), 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), 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
Glycerol, Male, Anaerobic Threshold, Phosphodiesterase Inhibitors, Physiology, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Adipose tissue, Octreotide, MESH: Phosphodiesterase Inhibitors, Catecholamines, 0302 clinical medicine, MESH: Aminophylline, Adrenergic alpha-2 Receptor Agonists, Insulin, MESH: Obesity, MESH: Lipid Metabolism, MESH: Anaerobic Threshold, 0303 health sciences, MESH: Adrenergic beta-Antagonists, Aminophylline, Adipose Tissue, MESH: Young Adult, MESH: Rest, MESH: Cyclic Nucleotide Phosphodiesterases, Type 3, Adrenergic alpha-Agonists, Anaerobic exercise, MESH: Adipose Tissue, medicine.drug, Adult, medicine.medical_specialty, Microdialysis, Rest, Adrenergic beta-Antagonists, 030209 endocrinology & metabolism, MESH: Insulin, Peptide hormone, Young Adult, 03 medical and health sciences, MESH: Glycerol, Physiology (medical), Internal medicine, MESH: Catecholamines, medicine, Humans, Lipolysis, Obesity, MESH: Natriuretic Peptides, Natriuretic Peptides, Exercise, Pancreatic hormone, 030304 developmental biology, MESH: Humans, MESH: Octreotide, business.industry, MESH: Adult, Lipid Metabolism, Cyclic Nucleotide Phosphodiesterases, Type 3, MESH: Male, Endocrinology, MESH: Exercise, Exercise Test, MESH: Adrenergic alpha-Agonists, MESH: Receptors, Adrenergic, alpha-2, MESH: Exercise Test, business
Abstract

International audience; The aim of this study was to evaluate the relative contributions of various hormones involved in the regulation of lipid mobilization in subcutaneous adipose tissue (SCAT) during exercise and to assess the impact of obesity on this regulation. Eight lean and eight obese men performed a 60-min cycle exercise bout at 50% of their peak oxygen uptake on two occasions: during intravenous infusion of octreotide (a somatostatin analog) or physiological saline (control condition). Lipolysis in SCAT was evaluated using in situ microdialysis. One microdialysis probe was perfused with the adrenergic blockers phentolamine and propranolol while another probe was perfused with the phosphodiesterase and adenosine receptor inhibitor aminophylline. Compared with the control condition, infusion of octreotide reduced plasma insulin levels in lean (from approximately 3.5 to 0.5 microU/ml) and in obese (from approximately 9 to 2 microU/ml), blunted the exercise-induced rise in plasma GH and epinephrine levels in both groups, and enhanced the exercise-induced natriuretic peptide (NP) levels in lean but not in obese subjects. In both groups, octreotide infusion resulted in higher exercise-induced increases in dialysate glycerol concentrations in the phentolamine-containing probe while no difference in lipolytic response was found in the aminophylline-containing probe. The results suggest that insulin antilipolytic action plays a role in the regulation of lipolysis during exercise in lean as well as in obese subjects. The octreotide-induced enhancement of exercise lipolysis in lean subjects was associated with an increased exercise-induced plasma NP response. Adenosine may contribute to the inhibition of basal lipolysis in both subject groups.

Published
2010

43. Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis

Author

Joao-Bosco Pesquero, David J. Salant, Stéphane Decramer, Eric Neau, J.P. Schanstra, Julie Klein, Peter Heeringa, Flavio Bandin, Jean-Loup Bascands, Julien Gonzalez, Groningen Kidney Center (GKC), Translational Immunology Groningen (TRIGR), 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), Service de Pédiatrie - Néphrologie, Médecine interne, Hypertension, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Department of Medicine, Boston University [Boston] (BU)-Evans Biomedical Research Center, Boston University [Boston] (BU), Department of Pathology and Medical Biology, University Medical Center Groningen [Groningen] (UMCG), Department of Biophysics, UNIFESP-Escola Paulista de Medicina, and Simon, Marie Francoise

Subjects
Male, Nephrology, Biopsy, MESH: Sulfonamides, MESH: Purpura, Schoenlein-Henoch, UP-REGULATION, Kidney, Receptor, Bradykinin B1, urologic and male genital diseases, ACTIVATION, MESH: Biopsy, Mice, Glomerulonephritis, MESH: Animals, MESH: Dioxoles, IN-VIVO, Sulfonamides, MOUSE MODEL, General Medicine, Kinin, MESH: Chemokines, MESH: Glomerulonephritis, HUMAN LUNG FIBROBLASTS, medicine.anatomical_structure, BRADYKININ B-1 RECEPTOR, Creatinine, REDUCES RENAL FIBROSIS, Chemokines, medicine.symptom, CRESCENTIC GLOMERULONEPHRITIS, medicine.medical_specialty, IgA Vasculitis, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Mice, Inbred Strains, Inflammation, MESH: Creatinine, Dioxoles, ENDOTOXIN-INDUCED INFLAMMATION, MESH: Mice, Inbred Strains, Nephropathy, MESH: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Internal medicine, medicine, Animals, Humans, RNA, Messenger, MESH: Mice, MESH: RNA, Messenger, Retrospective Studies, MESH: Receptor, Bradykinin B1, MESH: Humans, business.industry, Macrophages, MESH: Macrophages, MESH: Retrospective Studies, MESH: Kidney, medicine.disease, MESH: Male, Blockade, Bradykinin B1 Receptor Antagonists, Disease Models, Animal, Basic Research, Immunology, GLOMERULAR INJURY, MESH: Disease Models, Animal, business, Kidney disease
Abstract

International audience; Severe inflammation characterizes rapidly progressive glomerulonephritides, and expression of the kinin B1 receptor (B1R) associates with inflammation. Delayed B1R blockade reduces renal inflammation in a model of unilateral ureteral obstruction, but whether B1R modulates the pathophysiology of glomerulonephritides is unknown. Here, we observed an association of B1R protein expression and inflammation, in both glomeruli and the renal interstitium, in biopsies of patients with glomerulonephritides, Henoch-Schönlein purpura nephropathy, and ANCA-associated vasculitis. In the nephrotoxic serum-induced glomerulonephritis model, we observed upregulation of the B1R receptor; treatment with a B1R antagonist beginning 2 weeks after the onset of disease reduced both glomerular and tubular lesions and improved renal function. B1R blockade reduced renal chemokine expression and macrophage accumulation. Collectively, our data demonstrate that blockade of the kinin B1R has significant potential for the treatment of glomerulonephritis.

Published
2010

44. Mapping of the Fibroblast Growth Factors in Human White Adipose Tissue

Author

Peter Arner, Jean Galitzky, Ingrid Dahlman, Niklas Mejhert, Mikael Rydén, Keith N. Frayn, Lennart Blomqvist, Amanda T. Pettersson, Clara Bambace, Anne Bouloumié, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), 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), Division of Surgery, Department of Clinical Science, Karolinska Institutet [Stockholm]-Danderyds Hospital, Nuffield Department of Clinical Medicine [Oxford], University of Oxford, This work was supported by several grants from the Swedish Heart and Lung Foundation, the Swedish Research Council, the Swedish Diabetes Foundation, Storstockholms Diabetesfo¨ rening, Torsten och Ragnar So¨ derberg Foundation, Novo Nordisk Foundation, the European Union (HEPADIP, LSHM-CT-2005- 018734), ADAPT (HEALTH-F2-2008-201100), COST action (BM0602), NordForsk (SYSDIET-070014), and the Swedish Medical Association., European Project: 32591,HEPADIP, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Oxford [Oxford], 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, and Hepatic and adipose tissue and functions in the metabolic syndrome - HEPADIP - 32591 - OLD

Subjects
MESH: Heparin, FGF21, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Adipose tissue, White adipose tissue, Fibroblast growth factor, Polymerase Chain Reaction, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Adipocyte, Abdomen, FGF, MESH: Obesity, Oligonucleotide Array Sequence Analysis, 2. Zero hunger, 0303 health sciences, integumentary system, Chromosome Mapping, MESH: Enzyme-Linked Immunosorbent Assay, adipose tissue, MESH: Adipose Tissue, White, embryonic structures, MESH: Fibroblast Growth Factors, medicine.medical_specialty, Adipose Tissue, White, Enzyme-Linked Immunosorbent Assay, 030209 endocrinology & metabolism, Biology, MESH: Abdomen, 03 medical and health sciences, FGF9, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, RNA, Messenger, obesity, MESH: Overweight, MESH: RNA, Messenger, 030304 developmental biology, MESH: Humans, Heparin, Biochemistry (medical), MESH: Polymerase Chain Reaction, FGF18, Overweight, FGF1, Fibroblast Growth Factors, PPAR gamma, MESH: PPAR gamma, chemistry, MESH: Oligonucleotide Array Sequence Analysis, MESH: Chromosome Mapping
Abstract

Context: Fibroblast growth factors (FGFs) regulate the development of white adipose tissue (WAT). However, the secretion and cellular origin of individual FGFs in WAT as well as the influence of obesity are unknown. Objective: Our objective was to map FGFs in human sc WAT, the cellular source, and association with obesity. Design: Secretion, mRNA, and circulatory levels of FGFs in human abdominal sc WAT from nonobese and obese donors were examined by microarray, real-time quantitative PCR, and ELISA. The activity of FGFs in cultured human adipocytes was determined by phosphorylation assays. Results: Expression of five FGFs (FGF1, FGF2, FGF7, FGF9, and FGF18) and FGF homologous factor (FHF2) was identified in WAT. Only FGF1 was released in a time-dependent manner from sc WAT, and fat cells were the major source of FGF1 secretion. FGF1 expression increased and FGF2 decreased during adipocyte differentiation. Furthermore, FGF1 was not secreted into the circulation. Although FGF1 levels were 2-fold increased in obesity, they were unaltered by weight reduction. Only FGF1 and FGF2 induced a marked concentration-dependent phosphorylation of p44/42 in cultured human adipocytes. Conclusions: Of the investigated FGFs, only FGF1 is secreted from sc WAT and predominantly so from the adipocyte fraction. The activity in adipocyte cultures and lack of secretion into the circulation suggest that FGF1 acts as an auto- or paracrine factor. FGF1 levels are increased in obesity but unaffected by weight reduction, suggesting a primary defect in obese individuals. In conclusion, FGF1 may play a superior role among the FGFs in sc WAT and obesity development.

Published
2010

45. Activation of catalase by apelin prevents oxidative stress-linked cardiac hypertrophy

Author

Philippe Valet, Angelo Parini, Atul Pathak, Oksana Kunduzova, Céline Guilbeau-Frugier, Denis Calise, Camille Foussal, Olivier Lairez, 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), Service de Microchirurgie Expérimentale, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150), Service d'anatomie pathologique et histologie-cytologie [Rangueil], and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Pressure overload, MESH: Myocytes, Cardiac, Adipose tissue, medicine.disease_cause, Left ventricular hypertrophy, Biochemistry, Muscle hypertrophy, Mice, Structural Biology, Myocytes, Cardiac, MESH: Animals, chemistry.chemical_classification, MESH: Oxidative Stress, MESH: Hypertrophy, biology, Chemistry, MESH: Reactive Oxygen Species, Catalase, Apelin, MESH: Hydrogen Peroxide, Hypertrophy, Left Ventricular, MESH: Hypertrophy, Left Ventricular, Serotonin, medicine.medical_specialty, MESH: Myocardium, MESH: Rats, Biophysics, Cardiomegaly, Cardiomyocyte, MESH: Catalase, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, Molecular Biology, Reactive oxygen species, Myocardium, Hydrogen Peroxide, Hypertrophy, Cell Biology, medicine.disease, Rats, Oxidative Stress, Endocrinology, biology.protein, MESH: Serotonin, MESH: Cardiomegaly, Reactive Oxygen Species, Oxidative stress
Abstract

International audience; Adipose tissue secretes a variety of bioactive factors, which can regulate cardiomyocyte hypertrophy via reactive oxygen species (ROS). In the present study we investigated whether apelin affects ROS-dependent cardiac hypertrophy. In cardiomyocytes apelin inhibited the hypertrophic response to 5-HT and oxidative stress induced by 5-HT- or H(2)O(2) in a dose-dependent manner. These effects were concomitant to the increase in mRNA expression and activity of catalase. Chronic treatment of mice with apelin attenuated pressure-overload-induced left ventricular hypertrophy. The prevention of hypertrophy by apelin was associated with increased myocardial catalase activity and decreased plasma lipid hydroperoxide, as an index of oxidative stress. These results show that apelin behaves as a catalase activator and prevents cardiac ROS-dependent hypertrophy.

Published
2010

46. MicroRNA-21 Is Induced Early in Pancreatic Ductal Adenocarcinoma Precursor Lesions

Author

Pierre Cordelier, Talal Al Saati, Anny Souque, Janick Selves, Jérôme Torrisani, Arief A. Suriawinata, Nicolas Carrere, Mael Chalret du Rieu, Gregory J. Tsongalis, Louis Buscail, Marlène Dufresne, 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), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Dartmouth Medical School, Dartmouth Hitchcock Medical Center, Chirurgie Générale et Digestive [Purpan], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Pôle Maladies de l'appareil digestif [CHU Toulouse], and Simon, Marie Francoise

Subjects
Pathology, Pancreatic disease, endocrine system diseases, Clinical Biochemistry, Pancreatic Intraepithelial Neoplasia, medicine.disease_cause, MESH: Mice, Knockout, Mice, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Animals, MESH: In Situ Hybridization, Fluorescence, Epidermal growth factor receptor, In Situ Hybridization, Fluorescence, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, MESH: Reproducibility of Results, MESH: Pancreatic Neoplasms, KRAS, Carcinoma, Pancreatic Ductal, medicine.medical_specialty, MESH: Cell Line, Tumor, Ductal cells, Adenocarcinoma, Biology, Sensitivity and Specificity, MESH: Gene Expression Profiling, Cell Line, Tumor, microRNA, Biomarkers, Tumor, medicine, Carcinoma, Animals, Humans, MESH: Mice, MESH: Humans, MESH: Carcinoma, Pancreatic Ductal, Gene Expression Profiling, MESH: Adenocarcinoma, Biochemistry (medical), Reproducibility of Results, Cancer, [SDV.ETH] Life Sciences [q-bio]/Ethics, medicine.disease, digestive system diseases, MESH: Sensitivity and Specificity, [SDV.ETH]Life Sciences [q-bio]/Ethics, Pancreatic Neoplasms, Disease Models, Animal, MicroRNAs, MESH: Tumor Markers, Biological, biology.protein, MESH: Disease Models, Animal, MESH: MicroRNAs
Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) has the poorest overall prognosis among gastrointestinal cancers; however, curative resection in early-stage PDAC greatly improves survival rates, indicating the importance of early detection. Because abnormal microRNA production is commonly detected in cancer, we investigated noninvasive precursor pancreatic intraepithelial neoplasia (PanIN) lesions for microRNA production as a potential early biomarker of PDAC.Methods: Pathologists identified and classified ductal lesions. We extracted total RNA from laser-capture microdissected PanIN tissue samples from a conditional KRAS(G12D) mouse model (n = 29) or of human origin (n = 38) (KRAS is v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). MicroRNA production was quantified by quantitative real-time PCR. Internal controls included 5S and U6 RNAs.Results: Production of microRNAs miR-21, miR-205, and miR-200 paralleled PanIN progression in the KRAS(G12D) mouse model, compared with microRNA production in samples of nonpathologic ducts. miR-21 demonstrated the highest relative concentrations in the precursor lesions. Interestingly, miR-205 and miR-21 up-regulation preceded phenotypic changes in the ducts. The production of microRNAs miR-21, miR-221, miR-222, and let-7a increased with human PanIN grade, with peak production occurring in hyperplastic PanIN-2/3 lesions. In situ hybridization analysis indicated miR-21 production to be concentrated in pathologic ductal cells. miR-21 production was regulated by KRAS(G12D) and epidermal growth factor receptor in PDAC-derived cell lines.Conclusions: Aberrant microRNA production is an early event in the development of PanIN. Our findings indicate that miR-21 warrants further investigation as a marker for early detection of PDAC.

Published
2010

47. Cardiovascular autonomic neuropathy and other complications in type 1 diabetes

Author

Gérard Tap, Brigitte Guidolin, Jean-Michel Senard, Hélène Hanaire, Sébastien Fontaine, Anne Pavy-Le Traon, Simon, Marie Francoise, Unité de recherche sur les obésités, IFR 31 Louis Bugnard (IFR 31), Université Toulouse III - Paul Sabatier (UT3), 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)-Université Toulouse III - Paul Sabatier (UT3), 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 National de la Santé et de la Recherche Médicale (INSERM), Facteurs nerveux et structuration tissulaire, Université de Brest (UBO), Service d'explorations fonctionnelles, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), 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-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), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, medicine.medical_specialty, Valsalva Maneuver, medicine.medical_treatment, Blood Pressure, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Body Mass Index, Electrocardiography, 03 medical and health sciences, 0302 clinical medicine, Diabetic Neuropathies, Diabetes mellitus, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Valsalva maneuver, Humans, Heart rate variability, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Pure autonomic failure, Glycated Hemoglobin, Analysis of Variance, Type 1 diabetes, Models, Statistical, Hand Strength, Endocrine and Autonomic Systems, business.industry, fungi, food and beverages, Baroreflex, Middle Aged, medicine.disease, 3. Good health, Surgery, Diabetes Mellitus, Type 1, Logistic Models, Peripheral neuropathy, Erectile dysfunction, Autonomic Nervous System Diseases, Respiratory Mechanics, Cardiology, Regression Analysis, Female, Neurology (clinical), business, Diabetic Angiopathies, Retinopathy
Abstract

International audience; OBJECTIVE AND METHODS: This study deals with cardiovascular autonomic neuropathy (CAN) in type 1 diabetic patients and its association with other complications. We searched for CAN in 684 patients (age, 47 +/- 12 years; diabetes duration, 22 +/- 11 years) by cardiovascular responses to deep breathing and standing. Patients considered as positive had laboratory evaluation: "Ewing" tests (deep breathing, Valsalva, stand test, hand grip); heart rate variability (HRV) [low frequency (LF) and high frequency (HF) power] and spontaneous baroreflex slope (SBS). Logistic regression was used to identify the combination of patient characteristics, including other complications, most associated with CAN severity according to Ewing Score (ES 0-5). RESULTS: 66.2% presented no significant abnormality (ES 0-0.5), 21.5 % had mild abnormalities (ES 1-2), and 12.3% had confirmed autonomic failure (ES > 2). Decrease in LF, HF and SBS was highly correlated to CAN severity. In the stepwise regression, age, retinopathy, nephropathy, bladder dysfunction, erectile dysfunction, peripheral neuropathy and hypertension remained correlated with CAN, whereas digestive neuropathy, BMI and HbA1c were excluded. Despite a small number of events, we found a significant association between coronary disorders and CAN severity. CONCLUSIONS: Simple bedside tests can detect CAN. HRV and SBS provide additional elements on CAN severity. Diabetes duration did not discriminate sufficiently patients with CAN. The association with retinopathy is in favor of the role of poor glycemic control in CAN development. This study shows the interest of CAN detection and the need to look for extracardiac autonomic neuropathy and silent myocardial ischemia in patients with confirmed CAN.

Published
2010

48. Adipose Tissue Endothelial Cells From Obese Human Subjects: Differences Among Depots in Angiogenic, Metabolic, and Inflammatory Gene Expression and Cellular Senescence

Author

Aurélie Villaret, Tamara Tchkonia, Patrick Chiotasso, Coralie Sengenès, James L. Kirkland, David Estève, Marie Adeline Marques, Max Lafontan, Pauline Decaunes, Jean Galitzky, Anne Bouloumié, Laboratoires Sérobiologiques, Division of Cognis, 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), Chirurgie Générale et Digestive [Rangueil], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Robert and Arlene Kogod Center on Aging, Mayo Clinic, and Simon, Marie Francoise

Subjects
MESH: Inflammation, Male, CD31, Endothelial lipase, Biopsy, Endocrinology, Diabetes and Metabolism, Adipose tissue, 030204 cardiovascular system & hematology, MESH: Hypertension, Body Mass Index, MESH: Biopsy, 0302 clinical medicine, Reference Values, Adipocytes, MESH: Obesity, Cellular Senescence, 0303 health sciences, MESH: Middle Aged, MESH: Reference Values, MESH: Hypercholesterolemia, Middle Aged, MESH: Gene Expression Regulation, Immunohistochemistry, Endothelial stem cell, Vascular endothelial growth factor A, MESH: Cell Aging, Adipose Tissue, Hypertension, Female, medicine.symptom, tissues, Cell aging, MESH: Adipose Tissue, Adult, medicine.medical_specialty, Hypercholesterolemia, Subcutaneous Fat, Inflammation, Intra-Abdominal Fat, Biology, MESH: Body Mass Index, Proinflammatory cytokine, 03 medical and health sciences, MESH: Subcutaneous Fat, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Internal Medicine, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, MESH: Intra-Abdominal Fat, MESH: Adipocytes, 030304 developmental biology, MESH: Humans, Chemokine CCL20, nutritional and metabolic diseases, MESH: Immunohistochemistry, MESH: Adult, MESH: Chemokine CCL20, MESH: Male, Metabolism, Endocrinology, Gene Expression Regulation, MESH: Female
Abstract

OBJECTIVE Regional differences among adipose depots in capacities for fatty acid storage, susceptibility to hypoxia, and inflammation likely contribute to complications of obesity. We defined the properties of endothelial cells (EC) isolated from subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) biopsied in parallel from obese subjects. RESEARCH DESIGN AND METHODS The architecture and properties of the fat tissue capillary network were analyzed using immunohistochemistry and flow cytometry. CD34+/CD31+ EC were isolated by immunoselection/depletion. Expression of chemokines, adhesion molecules, angiogenic factor receptors, as well as lipogenic and senescence-related genes were assayed by real-time PCR. Fat cell size and expression of hypoxia-dependent genes were determined in adipocytes from both fat depots. RESULTS Hypoxia-related genes were more highly expressed in VAT than SAT adipocytes. VAT adipocytes were smaller than SAT adipocytes. Vascular density and EC abundance were higher in VAT. VAT-EC exhibited a marked angiogenic and inflammatory state with decreased expression of metabolism-related genes, including endothelial lipase, GPIHBP1, and PPAR gamma. VAT-EC had enhanced expression of the cellular senescence markers, IGFBP3 and γ-H2AX, and decreased expression of SIRT1. Exposure to VAT adipocytes caused more EC senescence-associated β-galactosidase activity than SAT adipocytes, an effect reduced in the presence of vascular endothelial growth factor A (VEGFA) neutralizing antibodies. CONCLUSIONS VAT-EC exhibit a more marked angiogenic and proinflammatory state than SAT-EC. This phenotype may be related to premature EC senescence. VAT-EC may contribute to hypoxia and inflammation in VAT.

Published
2010
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49. A Possible Inflammatory Role of Twist1 in Human White Adipocytes

Author

Amanda T. Pettersson, Anne Bouloumié, Mikael Rydén, Peter Arner, Ingrid Dahlman, Niklas Mejhert, Jurga Laurencikiene, Erik Näslund, Simon, Marie Francoise, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Division of Surgery, Department of Clinical Sciences, Karolinska Institutet [Stockholm]-Danderyds sjukhus = Danderyd University Hospital, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), 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, MESH: Oxidation-Reduction, Small interfering RNA, Endocrinology, Diabetes and Metabolism, Cellular differentiation, Adipocytes, White, Palmitates, Gene Expression, Adipose tissue, White adipose tissue, MESH: Down-Regulation, Mice, chemistry.chemical_compound, 0302 clinical medicine, Genes, Reporter, Adipocyte, MESH: RNA, Small Interfering, Gene expression, MESH: Animals, Carbon Radioisotopes, RNA, Small Interfering, Promoter Regions, Genetic, MESH: Carbon Radioisotopes, Beta oxidation, Chemokine CCL2, 0303 health sciences, MESH: Middle Aged, Nuclear Proteins, MESH: Twist Transcription Factor, Middle Aged, MESH: Adiponectin, Cell biology, 030220 oncology & carcinogenesis, Original Article, Female, Adiponectin, Oxidation-Reduction, Adult, medicine.medical_specialty, MESH: Gene Expression, animal structures, Lipolysis, Down-Regulation, Biology, 03 medical and health sciences, 3T3-L1 Cells, Internal medicine, MESH: Promoter Regions, Genetic, Internal Medicine, medicine, Animals, Humans, MESH: Lipolysis, MESH: Mice, MESH: Chemokine CCL2, 030304 developmental biology, MESH: Humans, Interleukin-6, Tumor Necrosis Factor-alpha, Twist-Related Protein 1, MESH: Genes, Reporter, MESH: Adult, MESH: Palmitates, MESH: Interleukin-6, MESH: 3T3-L1 Cells, MESH: Male, MESH: Adipocytes, White, Metabolism, Endocrinology, chemistry, MESH: Tumor Necrosis Factor-alpha, MESH: Nuclear Proteins, MESH: Female
Abstract

OBJECTIVE Twist1 is a transcription factor that is highly expressed in murine brown and white adipose tissue (WAT) and negatively regulates fatty acid oxidation in mice. The role of twist1 in WAT is not known and was therefore examined. RESEARCH DESIGN AND METHODS The expression of twist1 was determined by quantitative real-time PCR in different tissues and in different cell types within adipose tissue. The effect of twist1 small interfering RNA on fatty acid oxidation, lipolysis, adipokine secretion, and mRNA expression was determined in human adipocytes. The interaction between twist1 and specific promoters in human adipocytes was investigated by chromatin immunoprecipitation (ChIP) and reporter assays. RESULTS Twist1 was highly expressed in human WAT compared with a set of other tissues and found predominantly in adipocytes. Twist1 levels increased during in vitro differentiation of human preadipocytes. Gene silencing of twist1 in human white adipocytes had no effect on lipolysis or glucose transport. Unexpectedly, and in contrast with results in mice, twist1 RNA interference reduced fatty acid oxidation. Furthermore, the expression and secretion of the inflammatory factors tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1 were downregulated by twist1 silencing. ChIP and reporter assays confirmed twist1 interaction with the promoters of these genes. CONCLUSIONS Twist1 may play a role in inflammation of human WAT because it can regulate the expression and secretion of inflammatory adipokines via direct transcriptional effects in white adipocytes. Furthermore, twist1 may, in contrast to findings in mice, be a positive regulator of fatty acid oxidation in human white adipocytes.

Published
2009

50. HLA Class I Antibodies Provoke Graft Arteriosclerosis in Human Arteries Transplanted into SCID/Beige Mice

Author

Nassim Kamar, Lionel Rostaing, Sylvain Galvani, Mogens Thomsen, Jean-Claude Thiers, Y. Zou, Torsten Böhler, Michel Abbal, P. Stastny, Anne Nègre-Salvayre, Nathalie Augé, Cindy Canivet, Robert Salvayre, Federico Sallusto, Denis Calise, 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), Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Médecine Interne et immunologie clinique [CHU Toulouse], Pôle Maladies de l'appareil digestif [CHU Toulouse], University of Texas Southwestern Medical Center [Dallas], Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine [Rangueil], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Department of Multiorgan Transplantation, CHU Toulouse [Toulouse], and Department of Clinical Immunology

Subjects
Graft Rejection, Cellular immunity, Arteriosclerosis, [SDV]Life Sciences [q-bio], MESH: Mesenteric Arteries, Mice, SCID, 030230 surgery, Muscle, Smooth, Vascular, MESH: Histocompatibility Antigens Class I, Mice, 0302 clinical medicine, Immunology and Allergy, MESH: Animals, Pharmacology (medical), MESH: Mice, SCID, Mesenteric arteries, ComputingMilieux_MISCELLANEOUS, biology, MESH: Muscle, Smooth, Vascular, Mesenteric Arteries, 3. Good health, medicine.anatomical_structure, MESH: Cell Division, Antibody, Cell Division, Blood vessel, medicine.drug_class, Transplantation, Heterologous, Antibodies, Heterophile, MESH: Graft Rejection, Human leukocyte antigen, Monoclonal antibody, 03 medical and health sciences, medicine, Animals, Humans, MESH: Transplantation, Heterologous, MESH: Mice, Transplantation, MESH: Humans, business.industry, Histocompatibility Antigens Class I, MESH: Tunica Intima, medicine.disease, MESH: Arteriosclerosis, Immunology, biology.protein, Tunica Intima, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Antibodies, Heterophile, 030215 immunology
Abstract

International audience; Antibodies toward HLA class I and/or MICA are commonly observed in transplanted patients suffering from allograft arteriosclerosis, also called chronic vascular rejection (CVR). The relative importance of cellular versus humoral alloreactivity for CVR is still disputed. We demonstrate that antibodies toward HLA class I provoke lesions typical for CVR in human arteries in vivo in the absence of cellular immunity. To show this, we grafted segments of human mesenteric arteries from 8 deceased organ donors into 36 immunodeficient SCID/beige mice in the infrarenal aortic position. Three mice died postoperatively. The remaining 33 mice received weekly i.v. injections of either a monoclonal antibody toward HLA class I, toward MICA or an irrelevant monoclonal antibody. At sacrifice after 6 weeks, mice receiving the HLA antibody showed a significant neointimal thickening in the grafted artery due to smooth muscle cell (SMC) proliferation while control mice receiving anti-MICA or irrelevant antibody showed little or no thickening. Whereas antibodies toward HLA class I were mitogenic to SMC in vitro, those directed toward MICA did not have any effect. Humoral alloreactivity toward HLA may thus play a causal role for the development of CVR and this opens new possibilities for the treatment of CVR.

Published
2009

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