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Mol Metab. 2016 Nov 3;6(1):159-172. doi: 10.1016/j.molmet.2016.10.009. eCollection 2017 Jan.

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

Author information

1
Institut Cochin, Inserm U1016, CNRS UMR 8104, University Paris Descartes, Sorbonne Paris Cite, Paris, France.
2
University Paris Pierre et Marie Curie (UPMC), CNRS UMR 7091, NewVectys, Paris, France.
3
University Paris Diderot, Sorbonne Paris Cité, CNRS UMR8251, Paris, France.
4
Hiroshima University, Hiroshima, Japan.
5
University of Lille, CNRS UMR 8204, Inserm U1019, CHU Lille, Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France.
6
Assistance Publique des Hôpitaux de Paris (AP-HP), Université Paris Descartes, Inserm U942, Paris, France.
7
Institut Cochin, Inserm U1016, CNRS UMR 8104, University Paris Descartes, Sorbonne Paris Cite, Paris, France. Electronic address: julie.dam@inserm.fr.

Abstract

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.

KEYWORDS:

ARC, arcuate nucleus; BW, body weight; CD, chow diet; DIO, diet-induced obesity; Diabetes; Endo1, Endospanin1; GTT, glucose tolerance test; HFD, high fat diet; Insulin; LIF, leukemia inhibitory factor; Leptin receptor; OB-RGRP/Endospanin1; OBR, leptin receptor; Obesity; PLA, proximity ligation assay; T2D, type 2 diabetes; ip, intraperitoneal

PMID:
28123946
PMCID:
PMC5220283
DOI:
10.1016/j.molmet.2016.10.009
[Indexed for MEDLINE]
Free PMC Article

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