期刊
MOLECULAR METABOLISM
卷 6, 期 1, 页码 159-172出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.molmet.2016.10.009
关键词
Leptin receptor; OB-RGRP/Endospanin1; Insulin; Obesity; Diabetes
资金
- European Union [241592]
- Agence Nationale de la Recherche [ANR-12-JSV1-0011]
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Centre National de la Recherche Scientifique (CNRS)
- Ministere de l'Education Nationale et de la Recherche en Technologie (MNERT) [ED419]
- Fondation pour la Recherche Medicale
- Agence Nationale de la Recherche (ANR) [ANR-12-JSV1-0011] Funding Source: Agence Nationale de la Recherche (ANR)
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. (C) 2016 The Authors. Published by Elsevier GmbH.
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