Endospanin1 affects oppositely body weight regulation and glucose homeostasis by differentially regulating central leptin signaling
| Autor: | Jean-Marie Launay, Yves Rouillé, Patty Chen, Marc Foretz, Christophe Magnan, Ralf Jockers, Koichiro Ozawa, Stéphanie Migrenne, Jacques Mallet, Toru Hosoi, Clara Roujeau, Virginie Vauthier, Chamsy Sarkis, Julie Dam |
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| Přispěvatelé: | Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Hiroshima University, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Université Paris Descartes - Paris 5 (UPD5), 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 Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs ( LGMNPN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -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 ), Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 ( CIIL ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR142-Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), HAL UPMC, Gestionnaire |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Leptin
Male 0301 basic medicine OB-RGRP/Endospanin1 ip intraperitoneal medicine.medical_treatment Mice Obese Mice 0302 clinical medicine HFD high fat diet Homeostasis Glucose homeostasis Insulin Receptor [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism Glucose tolerance test Arc (protein) medicine.diagnostic_test BW body weight LIF leukemia inhibitory factor Diabetes Intracellular Signaling Peptides and Proteins [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism Leptin receptor Receptors Leptin GTT glucose tolerance test Original Article Signal Transduction STAT3 Transcription Factor lcsh:Internal medicine medicine.medical_specialty Hypothalamus T2D type 2 diabetes Biology Diet High-Fat ARC arcuate nucleus 03 medical and health sciences Internal medicine [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology medicine Animals [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Obesity lcsh:RC31-1245 Endo1 Endospanin1 Molecular Biology [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry Molecular Biology PI3K/AKT/mTOR pathway PLA proximity ligation assay Body Weight Arcuate Nucleus of Hypothalamus DIO diet-induced obesity Cell Biology OBR leptin receptor Mice Inbred C57BL Glucose 030104 developmental biology Endocrinology Diabetes Mellitus Type 2 CD chow diet Carrier Proteins 030217 neurology & neurosurgery |
| Zdroj: | Molecular metabolism Molecular metabolism, Elsevier, 2017, 6 (1), pp.159-172. ⟨10.1016/j.molmet.2016.10.009⟩ Molecular metabolism, 2017, 6 (1), pp.159-172. ⟨10.1016/j.molmet.2016.10.009⟩ Molecular metabolism, Elsevier, 2017, 6 (1), pp.159-172. 〈10.1016/j.molmet.2016.10.009〉 Molecular Metabolism Molecular Metabolism, Vol 6, Iss 1, Pp 159-172 (2017) |
| ISSN: | 2212-8778 |
| Popis: | The hypothalamic arcuate nucleus (ARC) is a major integration center for energy and glucose homeostasis that responds to leptin. Resistance to leptin in the ARC is an important component of the development of obesity and type 2 diabetes. Recently, we showed that Endospanin1 (Endo1) is a negative regulator of the leptin receptor (OBR) that interacts with OBR and retains the receptor inside the cell, leading to a decreased activation of the anorectic STAT3 pathway. Endo1 is up-regulated in the ARC of high fat diet (HFD)-fed mice, and its silencing in the ARC of lean and obese mice prevents and reverses the development of obesity. Objective Herein we investigated whether decreased Endo1 expression in the hypothalamic ARC, associated with reduced obesity, could also ameliorate glucose homeostasis accordingly. Methods We studied glucose homeostasis in lean or obese mice silenced for Endo1 in the ARC via stereotactic injection of shRNA-expressing lentiviral vectors. Results We observed that despite being leaner, Endo1-silenced mice showed impaired glucose homeostasis on HFD. Mechanistically, we show that Endo1 interacts with p85, the regulatory subunit of PI3K, and mediates leptin-induced PI3K activation. Conclusions Our results thus define Endo1 as an important hypothalamic integrator of leptin signaling, and its silencing differentially regulates the OBR-dependent functions. Highlights • Endospanin1 interacts with p85, the regulatory subunit of PI3K. • Endospanin1 silencing increases STAT3 but decreases AKT activation mediated by leptin. • Endospanin1 dissociates leptin-regulated body weight and glucose homeostasis. • Endospanin1 differentially regulates leptin signaling and biological functions. |
| Databáze: | OpenAIRE |
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