Elsevier

Molecular Metabolism

Volume 6, Issue 1, January 2017, Pages 159-172
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2016.10.009Get rights and content
Under a Creative Commons license
open access

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.

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

Leptin receptor
OB-RGRP/Endospanin1
Insulin
Obesity
Diabetes

Abbreviations

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

Cited by (0)

7

Equal contribution.