Endospanin1 affects oppositely body weight regulation and glucose homeostasis by differentially regulating central leptin signaling - Unité de Biologie Fonctionnelle et Adaptative Accéder directement au contenu
Article Dans Une Revue Molecular metabolism Année : 2017

Endospanin1 affects oppositely body weight regulation and glucose homeostasis by differentially regulating central leptin signaling

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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.
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hal-01501632 , version 1 (04-04-2017)

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Virginie Vauthier, Clara Roujeau, Patty Chen, Chamsy Sarkis, Stéphanie Migrenne, et al.. Endospanin1 affects oppositely body weight regulation and glucose homeostasis by differentially regulating central leptin signaling. Molecular metabolism, 2017, 6 (1), pp.159 - 172. ⟨10.1016/j.molmet.2016.10.009⟩. ⟨hal-01501632⟩
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