Silencing of OB-RGRP in Mouse Hypothalamic Arcuate Nucleus Increases Leptin Receptor Signaling and Prevents Diet-induced Obesity

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 Nov 29

PMID 18042720

Citations 47

Authors

Cyril Couturier

Chamsy Sarkis

Karin Seron

Sandrine Belouzard

Patty Chen

Aude Lenain

Laetitia Corset

Julie Dam

Virginie Vauthier

Anne Dubart

Jacques Mallet

Philippe Froguel

Yves Rouille

Ralf Jockers

Affiliations

Soon will be listed here.

Abstract

Obesity is a major public health problem and is often associated with type 2 diabetes mellitus, cardiovascular disease, and metabolic syndrome. Leptin is the crucial adipostatic hormone that controls food intake and body weight through the activation of specific leptin receptors (OB-R) in the hypothalamic arcuate nucleus (ARC). However, in most obese patients, high circulating levels of leptin fail to bring about weight loss. The prevention of this "leptin resistance" is a major goal for obesity research. We report here a successful prevention of diet-induced obesity (DIO) by silencing a negative regulator of OB-R function, the OB-R gene-related protein (OB-RGRP), whose transcript is genetically linked to the OB-R transcript. We provide in vitro evidence that OB-RGRP controls OB-R function by negatively regulating its cell surface expression. In the DIO mouse model, obesity was prevented by silencing OB-RGRP through stereotactic injection of a lentiviral vector encoding a shRNA directed against OB-RGRP in the ARC. This work demonstrates that OB-RGRP is a potential target for obesity treatment. Indeed, regulators of the receptor could be more appropriate targets than the receptor itself. This finding could serve as the basis for an approach to identifying potential new therapeutic targets for a variety of diseases, including obesity.

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