Glial Endozepines Reverse High-Fat Diet-Induced Obesity by Enhancing Hypothalamic Response to Peripheral Leptin

Autor: Guenievre Roussel, Bruno Lebrun, Vincent Prevot, Michel Dallaporta, Marie-Christine Tonon, Damien Lanfray, André Jean, Manon Duquenne, Florent Guillebaud, Jean-Denis Troadec, Seddik Riad, Mehdi Djelloul, Jérôme Leprince, Clément Pierre, Kevin Poirot, Stéphanie Gaigé, Fabrice Morin
Přispěvatelé: Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cell Stem Cell Laboratory for CNS Disease Modeling, Physiologie et physiopathologie du système nerveux somato-moteur et neurovégétatif (PPSN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Lund Stem Cell Center, Lund University [Lund]-Lund University [Lund], ANR-16-CE14-0011,EZICROM,Rôle des endozépines dans la régulation centrale normale et pathologique du métabolisme énergétique(2016)
Rok vydání: 2020
Předmět:
Zdroj: Molecular Neurobiology
Molecular Neurobiology, Humana Press, 2020, ⟨10.1007/s12035-020-01944-z⟩
Molecular Neurobiology, 2020, ⟨10.1007/s12035-020-01944-z⟩
ISSN: 1559-1182
0893-7648
Popis: Research on energy homeostasis has focused on neuronal signaling; however, the role of glial cells has remained little explored. Glial endozepines exert anorexigenic actions by mechanisms which remain poorly understood. In this context, the present study was designed to decipher the mechanisms underlying the anorexigenic action of endozepines and to investigate their potential curative effect on high-fat diet-induced obesity. We carried out a combination of physiological, pharmacological, and molecular analyses together to dissect the underlying mechanisms of endozepine-induced hypophagia. To evaluate the potential anti-obesity effect of endozepines, different model of obesity were used, i.e., ob/ob and diet-induced obese mice. We show that the intracerebral administration of endozepines enhances satiety by targeting anorexigenic brain circuitry and induces STAT3 phosphorylation, a hallmark of leptin signaling. Strikingly, endozepines are entirely ineffective at reducing food intake in the presence of a circulating leptin antagonist and in leptin-deficient mice (ob/ob) but potentiate the reduced food intake and weight loss induced by exogenous leptin administration in these animals. Endozepines reversed high fat diet-induced obesity by reducing food intake and restored leptin-induced STAT3 phosphorylation in the hypothalamus. Interestingly, we observed that glucose and insulin synergistically enhance tanycytic endozepine expression and release. Finally, endozepines, which induce ERK activation necessary for leptin transport into the brain in cultured tanycytes, require tanycytic leptin receptor expression to promote STAT3 phosphorylation in the hypothalamus. Our data identify endozepines as potential anti-obesity compounds in part through the modulation of the LepR-ERK-dependent tanycytic leptin shuttle.
Databáze: OpenAIRE
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