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1. Effects of dietary eicosapentaenoic acid (EPA) supplementation in high-fat fed mice on lipid metabolism and apelin/APJ system in skeletal muscle.

Author

Chantal Bertrand, Angelica Pignalosa, Estelle Wanecq, Chloé Rancoule, Aurélie Batut, Simon Deleruyelle, Lillà Lionetti, Philippe Valet, and Isabelle Castan-Laurell

Subjects
Medicine, Science
Abstract

Various studies have shown that eicosapentaenoic acid (EPA) has beneficial effects on obesity and associated disorders. Apelin, the ligand of APJ receptor also exerts insulin-sensitizing effects especially by improving muscle metabolism. EPA has been shown to increase apelin production in adipose tissue but its effects in muscle have not been addressed. Thus, the effects of EPA supplementation (36 g/kg EPA) in high-fat diet (HFD) (45% fat, 20% protein, 35% carbohydrate) were studied in mice with focus on muscle lipid metabolism and apelin/APJ expression. Compared with HFD mice, HFD+EPA mice had significantly less weight gain, fat mass, lower blood glucose, insulinemia and hepatic steatosis after 10 weeks of diet. In addition, EPA prevented muscle metabolism alterations since intramuscular triglycerides were decreased and β-oxidation increased. In soleus muscles of HFD+EPA mice, apelin and APJ expression were significantly increased compared to HFD mice. However, plasma apelin concentrations in HFD and HFD+EPA mice were similar. EPA-induced apelin expression was confirmed in differentiated C2C12 myocytes but in this model, apelin secretion was also increased in response to EPA treatment. In conclusion, EPA supplementation in HFD prevents obesity and metabolic alterations in mice, especially in skeletal muscle. Since EPA increases apelin/APJ expression in muscle, apelin may act in a paracrine/autocrine manner to contribute to these benefical effects.

Published
2013
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2. Upregulated Apelin Signaling in Pancreatic Cancer Activates Oncogenic Signaling Pathways to Promote Tumor Development

Author

Carline Chaves-Almagro, Johanna Auriau, Alizée Dortignac, Pascal Clerc, Hubert Lulka, Simon Deleruyelle, Fabrice Projetti, Jessica Nakhlé, Audrey Frances, Judit Berta, Véronique Gigoux, Daniel Fourmy, Marlène Dufresne, Anne Gomez-Brouchet, Julie Guillermet-Guibert, Pierre Cordelier, Bernard Knibiehler, Ralf Jockers, Philippe Valet, Yves Audigier, and Bernard Masri

Subjects
Apelin Receptors, Organic Chemistry, General Medicine, Oncogenes, Adenocarcinoma, Catalysis, Computer Science Applications, Receptors, G-Protein-Coupled, Inorganic Chemistry, Pancreatic Neoplasms, Mice, Phosphatidylinositol 3-Kinases, Glucose, pancreatic ductal adenocarcinoma, apelin, APJ, G protein-coupled receptor, signaling, oncogenes, Animals, Apelin, Humans, Cyclin D1, Physical and Theoretical Chemistry, Molecular Biology, Proto-Oncogene Proteins c-akt, Spectroscopy, beta Catenin, Carcinoma, Pancreatic Ductal, Signal Transduction
Abstract

Despite decades of effort in understanding pancreatic ductal adenocarcinoma (PDAC), there is still a lack of innovative targeted therapies for this devastating disease. Herein, we report the expression of apelin and its receptor, APJ, in human pancreatic adenocarcinoma and its protumoral function. Apelin and APJ protein expression in tumor tissues from patients with PDAC and their spatiotemporal pattern of expression in engineered mouse models of PDAC were investigated by immunohistochemistry. Apelin signaling function in tumor cells was characterized in pancreatic tumor cell lines by Western blot as well as proliferation, migration assays and in murine orthotopic xenograft experiments. In premalignant lesions, apelin was expressed in epithelial lesions whereas APJ was found in isolated cells tightly attached to premalignant lesions. However, in the invasive stage, apelin and APJ were co-expressed by tumor cells. In human tumor cells, apelin induced a long-lasting activation of PI3K/Akt, upregulated β-catenin and the oncogenes c-myc and cyclin D1 and promoted proliferation, migration and glucose uptake. Apelin receptor blockades reduced cancer cell proliferation along with a reduction in pancreatic tumor burden. These findings identify the apelin signaling pathway as a new actor for PDAC development and a novel therapeutic target for this incurable disease.

Published
2022
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3. Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor

Author

Jean Personnaz, Enzo Piccolo, Alizée Dortignac, Jason S. Iacovoni, Jérôme Mariette, Vincent Rocher, Arnaud Polizzi, Aurélie Batut, Simon Deleruyelle, Lucas Bourdens, Océane Delos, Lucie Combes-Soia, Romain Paccoud, Elsa Moreau, Frédéric Martins, Thomas Clouaire, Fadila Benhamed, Alexandra Montagner, Walter Wahli, Robert F. Schwabe, Armelle Yart, Isabelle Castan-Laurell, Justine Bertrand-Michel, Odile Burlet-Schiltz, Catherine Postic, Pierre-Damien Denechaud, Cédric Moro, Gaelle Legube, Chih-Hao Lee, Hervé Guillou, Philippe Valet, Cédric Dray, Jean-Philippe Pradère, Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Geroscience and rejuvenation research center (RESTORE), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Mathématiques et Informatique Appliquées de Toulouse (MIAT INRAE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), SIAAP - Direction du Développement et de la Prospective, SIAAP, Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), ToxAlim (ToxAlim), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Unité de biologie moléculaire, cellulaire et du développement - UMR5077 (MCD), 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), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Lee Kong Chian School of Medicine, Nanyang Technological University [Singapour], Columbia University [New York], MetaToul FluxoMet (TBI-MetaToul), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Harvard T.H. Chan School of Public Health, This study was supported by grants from INSERM, Paul Sabatier University, the Agence Nationale de la Recherche (ANR-17-CE14-0016, to J.-P.P.), and the Région Occitanie and Association Française d’Etude et de Recherche sur l’Obésité (to J.-P.P.). J.P. was supported by a scholarship from Paul Sabatier University. E.P. was supported by a scholarship from Agence Nationale de la Recherche (ANR-17-CE14-0016). R.P. was supported by a scholarship from Région Midi-Pyrénées-INSERM (no. 15050341). O.B.-S. and L.C.-S. and the proteomic facility were supported, in part, by the Région Occitanie, European funds (Fonds Européens de Développement Régional, FEDER), Toulouse Métropole, and the French Ministry of Research with the Investissement d’Avenir Infrastructures Nationales en Biologie et Santé program (ProFI, Proteomics French Infrastructure project, ANR-10-INBS-08), ANR-17-CE14-0016,HOLISTic,Rôle de la protéine HMGB1 au cours du stress metabolique(2017), and Lee Kong Chian School of Medicine (LKCMedicine)

Subjects
Fatty Liver, Multidisciplinary, [SDV]Life Sciences [q-bio], Medicine [Science], chemical and pharmacologic phenomena, Lipid Metabolisms
Abstract

Dysregulations of lipid metabolism in the liver may trigger steatosis progression, leading to potentially severe clinical consequences such as nonalcoholic fatty liver diseases (NAFLDs). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis. Mice with liver-specific Hmgb1 deficiency display exacerbated liver steatosis, while Hmgb1-overexpressing mice exhibited a protection from fatty liver progression when subjected to nutritional stress. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXRα and PPARγ activity. HMGB1 repression is not mediated through nucleosome landscape reorganization but rather via a preferential DNA occupation in a region carrying genes regulated by LXRα and PPARγ. Together, these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target the LXRα-PPARγ axis during NAFLD. Published version This study was supported by grants from INSERM, Paul Sabatier University, the Agence Nationale de la Recherche (ANR-17-CE14-0016, to J.-P.P.), and the Région Occitanie and Association Française d’Etude et de Recherche sur l’Obésité (to J.-P.P.). J.P. was supported by a scholarship from Paul Sabatier University. E.P. was supported by a scholarship from Agence Nationale de la Recherche (ANR-17-CE14-0016). R.P. was supported by a scholarship from Région Midi-Pyrénées-INSERM (no. 15050341). O.B.-S. and L.C.-S. and the proteomic facility were supported, in part, by the Région Occitanie, European funds (Fonds Européens de Développement Régional, FEDER), Toulouse Métropole, and the French Ministry of Research with the Investissement d’Avenir Infrastructures Nationales en Biologie et Santé program (ProFI, Proteomics French Infrastructure project, ANR-10-INBS-08).

Published
2022
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4. SHP2 drives inflammation-triggered insulin resistance by reshaping tissue macrophage populations

Author

Ophélie Pereira, Jean Personnaz, Céline Saint-Laurent, Toshiyuki Araki, Maithé Tauber, Jean-Pierre Salles, Philippe Valet, Adélaïde Gélineau, Mickaël Canouil, Romain Paccoud, Armelle Yart, Jacques Weill, Jean-Philippe Pradere, Mylène Tajan, Cédric Dray, Enzo Piccolo, Sophie Le Gonidec, Inès Baba, Thomas Edouard, Emmanuel L. Gautier, Haoussa Askia, Philippe Froguel, Benjamin G. Neel, Nicolas Beton, Simon Deleruyelle, Johanna Auriau, Sophie Branka, Alizée Dortignac, Maxime Branchereau, Isabelle Castan, Christophe Heymes, Rémy Burcelin, Julie Charpentier, Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Geroscience and rejuvenation research center (RESTORE), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan (CPTP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), ANR-17-CE14-0016,HOLISTic,Rôle de la protéine HMGB1 au cours du stress metabolique(2017), ANR-17-CE14-0009,CAPTOR,Contrôler la fonction des progéniteurs du tissu adipeux pour améliorer les désordres métaboliques de l'obésité(2017), and ANR-17-CE14-0023,TARGETKC,Homéostasie et rôles des cellules de Kupffer dans la stéatohépatite(2017)

Subjects
MESH: Inflammation, medicine.medical_specialty, endocrine system diseases, education, Inflammation, Type 2 diabetes, MESH: Mice, Knockout, Diabetes Mellitus, Experimental, Proinflammatory cytokine, Mice, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, MESH: Diabetes Mellitus, Experimental, medicine, Animals, Humans, Glucose homeostasis, MESH: Animals, Macrophage homeostasis, MESH: Mice, 030304 developmental biology, Mice, Knockout, 0303 health sciences, MESH: Humans, business.industry, Macrophages, Monocyte, nutritional and metabolic diseases, MESH: Macrophages, General Medicine, medicine.disease, 3. Good health, MESH: Insulin Resistance, medicine.anatomical_structure, Endocrinology, Adipose Tissue, Diabetes Mellitus, Type 2, Lipotoxicity, Insulin Resistance, medicine.symptom, business, MESH: Adipose Tissue, 030217 neurology & neurosurgery, MESH: Diabetes Mellitus, Type 2
Abstract

Insulin resistance is a key event in type 2 diabetes onset and a major comorbidity of obesity. It results from a combination of fat excess-triggered defects, including lipotoxicity and metaflammation, but the causal mechanisms remain difficult to identify. Here, we report that hyperactivation of the tyrosine phosphatase SHP2 found in Noonan syndrome (NS) led to an unsuspected insulin resistance profile uncoupled from altered lipid management (for example, obesity or ectopic lipid deposits) in both patients and mice. Functional exploration of an NS mouse model revealed this insulin resistance phenotype correlated with constitutive inflammation of tissues involved in the regulation of glucose metabolism. Bone marrow transplantation and macrophage depletion improved glucose homeostasis and decreased metaflammation in the mice, highlighting a key role of macrophages. In-depth analysis of bone marrow-derived macrophages in vitro and liver macrophages showed that hyperactive SHP2 promoted a proinflammatory phenotype, modified resident macrophage homeostasis, and triggered monocyte infiltration. Consistent with a role of SHP2 in promoting inflammation-driven insulin resistance, pharmaceutical SHP2 inhibition in obese diabetic mice improved insulin sensitivity even better than conventional antidiabetic molecules by specifically reducing metaflammation and alleviating macrophage activation. Together, these results reveal that SHP2 hyperactivation leads to inflammation-triggered metabolic impairments and highlight the therapeutical potential of SHP2 inhibition to ameliorate insulin resistance.

Published
2021
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5. Nuclear HMGB1 protects from non-alcoholic fatty liver diseases through negative regulation of liver X receptor

Author

Romain Paccoud, Arnaud Polizzi, Isabelle Castan-Laurell, Jérôme Mariette, Robert F. Schwabe, W. Wahli, Frédéric Martins, Jason S. Iacovoni, Enzo Piccolo, Thomas Clouaire, Simon Deleruyelle, Chih-Hao Lee, Philippe Valet, Jean-Philippe Pradere, Gaëlle Legube, Fadila Benhamed, Hervé Guillou, Alexandra Montagner, Cedric Moro, Catherine Postic, Jean Personnaz, Elsa Moreau, Cédric Dray, Alizee Dortignac, Armelle Yart, and Aurélie Batut

Subjects
medicine.medical_specialty, Fatty liver, chemical and pharmacologic phenomena, Lipid metabolism, Biology, medicine.disease, Transcriptome, Endocrinology, Insulin resistance, Internal medicine, Lipogenesis, medicine, Steatosis, Liver X receptor, Transcription factor
Abstract

Dysregulations of lipid metabolism in the liver may trigger steatosis progression leading to potentially severe clinical consequences such as non-alcoholic fatty liver diseases (NAFLD). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and the activity of multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis during metabolic stress in NAFLD. Mice with liver-specific Hmgb1-deficiency display exacerbated liver steatosis and hepatic insulin resistance when subjected to a high-fat diet or after fasting/refeeding. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXRα activity resulting in increased lipogenesis. HMGB1 repression is not mediated through nucleosome landscape re-organization but rather via a preferential DNA occupation in region carrying genes regulated by LXRα. Together these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target LXRα axis during NAFLD.

Published
2021
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6. Chronic apelin treatment improves hepatic lipid metabolism in obese and insulin-resistant mice by an indirect mechanism

Author

Sophie Le Gonidec, Philippe Valet, Nancy Geoffre, Jean-Philippe Pradere, Jean Personnaz, Cedric Moro, Isabelle Castan-Laurell, C. Bertrand, Aurélie Batut, Katie Louche, Simon Deleruyelle, Bernard Masri, Unité de recherche sur les obésités, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Hormones, facteurs de croissance et physiopathologie vasculaire, Plateau MetaToul-LIPIDOMIQUE = MetaToul-Lipidomics, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), 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)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Vétérinaire de Toulouse (ENVT)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Type 2 diabetes, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mice, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin resistance, Internal medicine, Diabetes mellitus, Animals, Medicine, Obesity, Triglycerides, ComputingMilieux_MISCELLANEOUS, Apelin receptor, business.industry, Fatty liver, Lipid metabolism, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Lipid Metabolism, medicine.disease, 3. Good health, Apelin, Fatty Liver, 030104 developmental biology, Liver, 030220 oncology & carcinogenesis, Hepatocytes, Insulin Resistance, Steatosis, Energy Metabolism, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Apelin treatment has been shown to improve insulin sensitivity in insulin resistant mice by acting in skeletal muscles. However, the effects of systemic apelin on the hepatic energy metabolism have not been addressed. We thus aimed to determine the effect of chronic apelin treatment on the hepatic lipid metabolism in insulin resistant mice. The apelin receptor (APJ) expression was also studied in this context since its regulation has only been reported in severe liver pathologies. Mice were fed a high-fat diet (HFD) in order to become obese and insulin resistant compared to chow fed mice (CD). HFD mice then received a daily intraperitoneal injection of apelin (0.1 µmol/kg) or PBS during 28 days. Triglycerides content and the expression of different lipogenesis-related genes were significantly decreased in the liver of HFD apelin-treated compared to PBS-treated mice. Moreover, at this stage of insulin resistance, the beta-oxidation was increased in liver homogenates of HFD PBS-treated mice compared to CD mice and reduced in HFD apelin-treated mice. Finally, APJ expression was not up-regulated in the liver of insulin resistant mice. In isolated hepatocytes from chow and HFD fed mice, apelin did not induce significant effect. Altogether, these results suggest that systemic apelin treatment decreases steatosis in insulin resistant mice without directly targeting hepatocytes.

Published
2018
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7. The exerkine apelin reverses age-associated sarcopenia

Author

Cédric Dray, Vincent Mouly, Jerome N. Feige, Marco Pahor, Laura Lukjanenko, Philippe Valet, Simon Deleruyelle, Angèle Chopard, Ophélie Pereira, Umji Lee, Nancy Geoffre, Jean-Philippe Pradere, Karima Chaoui, Etienne Mouisel, Mathieu Vigneau, Fabien Pillard, Sonia Karaz, Matteo Cesari, Sophie Le Gonidec, Alizée Dortignac, Mylène Camus, Bruno Vellas, Allan F. Pagano, Sophie Guyonnet, Anne Bigot, Claire Vinel, Aurélie Batut, Odile Burlet-Schiltz, 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, Aging Dept, Nestle Inst Hlth Sci SA, Innovat Pk, Ecole Polytechnique Fédérale de Lausanne (EPFL), 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), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Dynamique Musculaire et Métabolisme (DMEM), Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM), Gérontopôle, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Coll Med, Inst Aging, University of Florida [Gainesville] (UF), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse], U1048, Inst Malad Metabol & Cardiovasc, Institut National de la Santé et de la Recherche Médicale (INSERM), UM76, Inst Myol, UMR7215, UMRS 974, Université Pierre et Marie Curie (Paris 6), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA), and University of Florida [Gainesville]

Subjects
0301 basic medicine, Aging, Sarcopenia, [SDV]Life Sciences [q-bio], Adipose tissue, physical activity, 0302 clinical medicine, regenerative capacity, Aged, 80 and over, satellite cells, Apelin Receptors, Muscle Weakness, Organelle Biogenesis, Ribosomal Protein S6 Kinases, 70-kDa, General Medicine, 3. Good health, Apelin, adipose tissue, medicine.anatomical_structure, medicine.symptom, Stem cell, Muscle contraction, Adult, medicine.medical_specialty, Adolescent, Satellite Cells, Skeletal Muscle, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Internal medicine, medicine, Animals, Humans, Regeneration, skeletal muscle, Muscle, Skeletal, Exercise, Aged, Muscle Cells, business.industry, Adenylate Kinase, Body Weight, Autophagy, Muscle weakness, Skeletal muscle, medicine.disease, Mice, Inbred C57BL, Kinetics, 030104 developmental biology, Endocrinology, Protein Biosynthesis, business, Proto-Oncogene Proteins c-akt, 030217 neurology & neurosurgery
Abstract

Sarcopenia, the degenerative loss of skeletal muscle mass, quality and strength, lacks early diagnostic tools and new therapeutic strategies to prevent the frailty-to-disability transition often responsible for the medical institutionalization of elderly individuals. Herein we report that production of the endogenous peptide apelin, induced by muscle contraction, is reduced in an age-dependent manner in humans and rodents and is positively associated with the beneficial effects of exercise in older persons. Mice deficient in either apelin or its receptor (APLNR) presented dramatic alterations in muscle function with increasing age. Various strategies that restored apelin signaling during aging further demonstrated that this peptide considerably enhanced muscle function by triggering mitochondriogenesis, autophagy and anti-inflammatory pathways in myofibers as well as enhancing the regenerative capacity by targeting muscle stem cells. Taken together, these findings revealed positive regulatory feedback between physical activity, apelin and muscle function and identified apelin both as a tool for diagnosis of early sarcopenia and as the target of an innovative pharmacological strategy to prevent age-associated muscle weakness and restore physical autonomy.

Published
2018
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8. Diet-induced obesity and associated disorders are prevented by natural bioactive type 1 fish collagen peptides (Naticol®) treatment

Author

Gwendoline Astre, Christelle Bonnet, Philippe Valet, Alizée Dortignac, Cédric Dray, and Simon Deleruyelle

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Panniculitis, Physiology, Lipolysis, 030209 endocrinology & metabolism, Context (language use), Diet, High-Fat, Weight Gain, Biochemistry, Proinflammatory cytokine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Insulin resistance, Internal medicine, Adipocyte, Glucose Intolerance, medicine, Animals, Fish Proteins, Dietary, Obesity, Cholesterol, Anti-Inflammatory Agents, Non-Steroidal, General Medicine, Metabolism, medicine.disease, Peptide Fragments, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, chemistry, Adipose Tissue, Gene Expression Regulation, Dietary Supplements, Apelin, Cytokines, Anti-Obesity Agents, Collagen, Insulin Resistance, Hormone
Abstract

To fight against metabolic disorders such as insulin resistance, new alimentary behaviors are developed. For instance, hyperproteined, gluten-free, or collagen-enriched diets could be preconized in order to reduce the consequences of obesity. In this aim, this study evaluates the potential effects of warm sea fish collagen peptides (Naticol®) on representative metabolic and inflammatory parameters. For that, male C57Bl6/J mice fed with either a chow- (CD) or high-fat diet (HFD) were submitted or not to specific collagen peptides in drinking water (4 g/kg bw/d) for 20 weeks. Weight, body composition, glucose tolerance, and insulin sensitivity were followed up. Effects of fish collagen peptides on various blood parameters reflecting the metabolism status were also measured (free fatty acids, triglycerides, cholesterol, hormones) together with adipocyte inflammation. Results showed that HFD-fed mice supplemented by fish collagen peptides exhibited a significant lower increase in body weight as soon as the twelfth week of treatment whereas no effect of the peptide was observed in CD fed mice. In line with this result, a weaker increase in fat mass in HFD-fed mice supplemented with Naticol® at both 9 and 18 weeks of treatment was also observed. In spite of this resistance to obesity promoted by fish collagen peptides treatment, no difference in glucose tolerance was found between groups whereas mice treated with Naticol® exhibited a lower basal glycemia. Also, even if no effect of the treatment on adipocyte lipolysis was found, a decrease of inflammatory cytokines was retrieved in collagen-supplemented group arguing for a potential better insulin sensitivity. Altogether, these results need to be completed but are the first describing a benefic role of warm sea fish collagen peptides in a context of metabolic disease paving the route for a potential utilization in human obesity-associated disorders.

Published
2017

9. Piceatannol and resveratrol share inhibitory effects on hydrogen peroxide release, monoamine oxidase and lipogenic activities in adipose tissue, but differ in their antilipolytic properties

Author

Pascale Mauriège, Simon Deleruyelle, Picard Marceau, Francisco Les, Jean A. Boutin, Christian Carpéné, Balázs Balogh, Françoise Nepveu, Denis Richard, Simon Biron, Laure-Estelle Cassagnes, Jose M. Arbones-Mainar, 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), Universidad San Jorge, Hôpital de Rangueil, CHU Toulouse [Toulouse], Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), Institut de Recherches SERVIER (IRS), Semmelweis University [Budapest], Instituto Aragonés de Ciencias de la Salud [Zaragoza] (IACS), Faculté de médecine de l'Université Laval [Québec] (ULaval), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Université Laval [Québec] (ULaval), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Biotechnologies, Pharamcologie Moléculaire et Cellulaire, Institut de Recherches Servier, Laboratoire de Logique, Algorithmique et Informatique (LLAIC1), Université d'Auvergne - Clermont-Ferrand I (UdA), Institut de médecine moléculaire de Rangueil (I2MR), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, 0301 basic medicine, Benzylamines, Amine oxidase, Monoamine oxidase, Lipolysis, [SDV]Life Sciences [q-bio], Amine oxidases, Subcutaneous Fat, Tyramine, Adipose tissue, Resveratrol, Toxicology, Dietary stilbenes, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Adipocyte, Stilbenes, Adipocytes, Animals, Humans, Obesity, Monoamine Oxidase, ComputingMilieux_MISCELLANEOUS, Piceatannol, biology, Lipogenesis, Electron Spin Resonance Spectroscopy, food and beverages, General Medicine, Catalase, Oxidants, Hydrogen peroxide, Mice, Inbred C57BL, Molecular Docking Simulation, 030104 developmental biology, chemistry, Biochemistry, Oxidative stress, 030220 oncology & carcinogenesis, Adipocyte lipolysis, Biocatalysis, biology.protein, Female
Abstract

International audience; Piceatannol is a hydroxylated derivative of resveratrol. While both dietary polyphenols coexist in edible plants and fruits, and share equivalent concentrations in several wines, the influence of piceatannol on adiposity has been less studied than that of resveratrol. Though resveratrol is now recognized to limit fat deposition in various obesity models, the benefit of its dietary supplementation remains under debate regarding human obesity treatment or prevention. The research for more potent resveratrol analogs is therefore still undergoing. This prompted us to compare various effects of piceatannol and resveratrol directly on human adipose tissue (hAT). Hydrogen peroxide release was measured by Amplex Red-based fluorescence in subcutaneous hAT samples from obese patients. Interactions of stilbenes with human amine oxidases and quinone reductase were assessed by radiometric methods, computational docking and electron paramagnetic resonance. Influences on lipogenic and lipolytic activities were compared in mouse adipocytes. Resveratrol and piceatannol inhibited monoamine oxidase (MAO) with respective IC50 of 18.5 and 133.7 μM, but not semicarbazide-sensitive amine oxidase (SSAO) in hAT. For both stilbenes, the docking scores were better for MAO than for SSAO. Piceatannol and resveratrol similarly hampered hydrogen peroxide detection in assays with and without hAT, while they shared pro-oxidant activities when incubated with purified quinone reductase. They exhibited similar dose-dependent inhibition of adipocyte lipogenic activity. Only piceatannol inhibited basal and stimulated lipolysis when incubated at a dose ≥100 μM. Thus, piceatannol exerted on fat cells dose-dependent effects similar to those of resveratrol, except for a stronger antilipolytic action. In this regard, piceatannol should be useful in limiting the lipotoxicity related to obesity when ingested or administered alone - or might hamper the fat mobilization induced by resveratrol when simultaneously administered with it.

Published
2016
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10. Une inflammation systémique conduit à un phénotype insoupçonné d’intolérance au glucose dans le syndrome de Noonan

Author

S. Branka, J.P. Pradère, Philippe Valet, I. Castan, R. Paccoud, M. Tajan, Simon Deleruyelle, Thomas Edouard, and Armelle Yart

Subjects
Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract

Objectif Les mutations « gain de fonction » dans le gene Ptpn11 codant pour SHP2 sont responsables du syndrome de Noonan (SN), une maladie genetique rare caracterisee par de multiples defauts developpementaux, notamment un retard de croissance, des cardiopathies et des desordres myeloproliferatifs. SHP2 est une tyrosine phosphatase qui regule des voies de signalisation majeures (MAPK, PI3K), jouant ainsi des roles pleiotropiques dans le developpement, l’homeostasie et le metabolisme. Si les consequences developpementales induites par les mutations de SHP2 responsables du SN sont bien connues, leur impact sur le metabolisme n’a jamais ete etudie. Methode L’etude a ete realisee sur un modele murin du SN (Ptpn11D61G/+), portant a l’etat heterozygote la mutation D61G, frequemment retrouvee chez les patients, ainsi que sur une cohorte de patients. Resultats Nous avons mis en evidence un phenotype metabolique inattendu, associant une adiposite reduite et une intolerance au glucose/resistance a l’insuline, aussi bien dans le modele murin que chez les patients. Bien qu’elles ne presentent aucun signe de lipotoxicite, les souris SN developpent une inflammation de leurs tissus metaboliques. Une transplantation de moelle osseuse ou une depletion des macrophages par du clodronate permettent de normaliser l’intolerance au glucose. Conclusion Nous avons identifie un phenotype metabolique original qui decouple la resistance a l’insuline provoquee par l’inflammation de l’aspect adiposite. Ceci ouvre de nouvelles perspectives dans la physiopathologie du SN et, au-dela du contexte des maladies rares, dans la comprehension des mecanismes impliques dans les maladies metaboliques.

Published
2018
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11. Effects of Dietary Eicosapentaenoic Acid (EPA) Supplementation in High-Fat Fed Mice on Lipid Metabolism and Apelin/APJ System in Skeletal Muscle

Author

Angelica Pignalosa, Philippe Valet, Isabelle Castan-Laurell, Chloé Rancoule, Simon Deleruyelle, Aurélie Batut, C. Bertrand, Estelle Wanecq, Lillà Lionetti, Chantal, Bertrand, Pignalosa, Angelica, Estelle, Wanecq, Chloè, Rancoule, Aurèlie, Batut, Simon, Deleruyelle, Lionetti, Lilla', Philippe, Valet, and Isabelle Castan, Laurell

Subjects
Blood Glucose, Male, medicine.medical_specialty, insulin resistant mice, Muscle Proteins, lcsh:Medicine, Adipose tissue, Adipokine, Biology, complex mixtures, Cell Line, Mice, Adipokines, Internal medicine, medicine, Animals, Myocyte, Obesity, Muscle, Skeletal, lcsh:Science, health care economics and organizations, Multidisciplinary, lcsh:R, Skeletal muscle, Lipid metabolism, social sciences, medicine.disease, Dietary Fats, Eicosapentaenoic acid, Apelin, Endocrinology, medicine.anatomical_structure, Eicosapentaenoic Acid, Gene Expression Regulation, Dietary Supplements, Intercellular Signaling Peptides and Proteins, upregulates apelin, lcsh:Q, lipids (amino acids, peptides, and proteins), Steatosis, Research Article
Abstract

Various studies have shown that eicosapentaenoic acid (EPA) has beneficial effects on obesity and associated disorders. Apelin, the ligand of APJ receptor also exerts insulin-sensitizing effects especially by improving muscle metabolism. EPA has been shown to increase apelin production in adipose tissue but its effects in muscle have not been addressed. Thus, the effects of EPA supplementation (36 g/kg EPA) in high-fat diet (HFD) (45% fat, 20% protein, 35% carbohydrate) were studied in mice with focus on muscle lipid metabolism and apelin/APJ expression. Compared with HFD mice, HFD+EPA mice had significantly less weight gain, fat mass, lower blood glucose, insulinemia and hepatic steatosis after 10 weeks of diet. In addition, EPA prevented muscle metabolism alterations since intramuscular triglycerides were decreased and β-oxidation increased. In soleus muscles of HFD+EPA mice, apelin and APJ expression were significantly increased compared to HFD mice. However, plasma apelin concentrations in HFD and HFD+EPA mice were similar. EPA-induced apelin expression was confirmed in differentiated C2C12 myocytes but in this model, apelin secretion was also increased in response to EPA treatment. In conclusion, EPA supplementation in HFD prevents obesity and metabolic alterations in mice, especially in skeletal muscle. Since EPA increases apelin/APJ expression in muscle, apelin may act in a paracrine/autocrine manner to contribute to these benefical effects.

Published
2013

12. LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity

Author

Patrick Raynal, Karine Tréguer, Maithé Tauber, Mylène Tajan, Philippe Valet, Aurélie Batut, Sophie Le Gonidec, Marie-Adeline Marques, Armelle Yart, Thomas Edouard, Céline Saint Laurent, Claire Vinel, Jean-Pierre Salles, Oksana Kunduzova, Thomas Cadoudal, Hélène Cavé, Joffrey Pozzo, Estelle Wanecq, Simon Deleruyelle, Maëlle Vomscheid, Audrey De Rocca Serra-Nédélec, Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), and Université Toulouse - Jean Jaurès (UT2J)

Subjects
Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Lipolysis, MAP Kinase Kinase Kinase 1, Mice, Transgenic, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Biology, medicine.disease_cause, LEOPARD Syndrome, Short stature, Mice, Thinness, Internal medicine, medicine, Adipocytes, Animals, Insulin, Obesity, Hypertelorism, ComputingMilieux_MISCELLANEOUS, Adiposity, 2. Zero hunger, Recombination, Genetic, Mutation, Multidisciplinary, Lentivirus, Cell Differentiation, medicine.disease, Phenotype, 3. Good health, Diet, PTPN11, Insulin receptor, Disease Models, Animal, Endocrinology, PNAS Plus, Adipose Tissue, biology.protein, Body Composition, medicine.symptom, Energy Metabolism, Noonan Syndrome with Multiple Lentigines
Abstract

LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS), also called Noonan syndrome with multiple lentigines (NSML), is a rare autosomal dominant disorder associating various developmental defects, notably cardiopathies, dysmorphism, and short stature. It is mainly caused by mutations of the PTPN11 gene that catalytically inactivate the tyrosine phosphatase SHP2 (Src-homology 2 domain-containing phosphatase 2). Besides its pleiotropic roles during development, SHP2 plays key functions in energetic metabolism regulation. However, the metabolic outcomes of LS mutations have never been examined. Therefore, we performed an extensive metabolic exploration of an original LS mouse model, expressing the T468M mutation of SHP2, frequently borne by LS patients. Our results reveal that, besides expected symptoms, LS animals display a strong reduction of adiposity and resistance to diet-induced obesity, associated with overall better metabolic profile. We provide evidence that LS mutant expression impairs adipogenesis, triggers energy expenditure, and enhances insulin signaling, three features that can contribute to the lean phenotype of LS mice. Interestingly, chronic treatment of LS mice with low doses of MEK inhibitor, but not rapamycin, resulted in weight and adiposity gains. Importantly, preliminary data in a French cohort of LS patients suggests that most of them have lower-than-average body mass index, associated, for tested patients, with reduced adiposity. Altogether, these findings unravel previously unidentified characteristics for LS, which could represent a metabolic benefit for patients, but may also participate to the development or worsening of some traits of the disease. Beyond LS, they also highlight a protective role of SHP2 global LS-mimicking modulation toward the development of obesity and associated disorders.

Published
2014
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