Regulation of insulin and leptin signaling by muscle suppressor of cytokine signaling 3 (SOCS3).

Zhenggang Yang,Lingzhi Cai,Hang Shi,Erin E Kershaw,Matthew Hulver,Bingzhong Xue,Liqing Yu,Ryan P Mcmillan,Thierry Alquier

doi:10.1371/journal.pone.0047493

Abstract

Skeletal muscle resistance to the key metabolic hormones, leptin and insulin, is an early defect in obesity. Suppressor of cytokine signaling 3 (SOCS3) is a major negative regulator of both leptin and insulin signaling, thereby implicating SOCS3 in the pathogenesis of obesity and associated metabolic abnormalities. Here, we demonstrate that SOCS3 mRNA expression is increased in murine skeletal muscle in the setting of diet-induced and genetic obesity, inflammation, and hyperlipidemia. To further evaluate the contribution of muscle SOCS3 to leptin and insulin resistance in obesity, we generated transgenic mice with muscle-specific overexpression of SOCS3 (MCK/SOCS3 mice). Despite similar body weight, MCK/SOCS3 mice develop impaired systemic and muscle-specific glucose homeostasis and insulin action based on glucose and insulin tolerance tests, hyperinsulinemic-euglycemic clamps, and insulin signaling studies. With regards to leptin action, MCK/SOCS3 mice exhibit suppressed basal and leptin-stimulated activity and phosphorylation of alpha2 AMP-activated protein kinase (α2AMPK) and its downstream target, acetyl-CoA carboxylase (ACC). Muscle SOCS3 overexpression also suppresses leptin-regulated genes involved in fatty acid oxidation and mitochondrial function. These studies demonstrate that SOC3 within skeletal muscle is a critical regulator of leptin and insulin action and that increased SOCS may mediate insulin and leptin resistance in obesity.

Highlights

Obesity, a disorder of impaired energy metabolism, is highly associated with insulin resistance and overt type 2 diabetes mellitus [1]
We found that Suppressor of cytokine signaling 3 (SOCS3) overexpression decreased mRNA expression of such genes, including carnitine palmitoyl transferase 1 (CPT1), peroxisome proliferator-activated receptor a (PPARa), cytochrome C oxidase I (COXI), and acyl-CoA oxidase (ACOX), in soleus muscle (Fig. 5C)
SOCS3 is a single molecule that mediates both leptin and insulin resistance due to its ability to down-regulate leptin and insulin signaling. These data are the first to demonstrate that SOCS3 antagonizes both leptin and insulin signaling in skeletal muscle, which is a principal site of glucose and fatty acid use and is one of the primary tissues responsible for insulin resistance in obesity [5]

Summary

Introduction

A disorder of impaired energy metabolism, is highly associated with insulin resistance and overt type 2 diabetes mellitus [1]. There is considerable evidence that energy balance and glucose homeostasis are physiologically regulated by the key metabolic hormones leptin and insulin, whose signaling network and ultimate action are interconnected in multiple tissues [1]. Insulin and/or leptin resistance in skeletal muscle may play a significant role in the pathogenesis of obesity and type 2 diabetes. The role of SOCS3 in skeletal muscle, a key tissue contributing to obesity and insulin resistance, is not known. We hypothesize that skeletal muscle SOCS3 contributes to obesity and insulin resistance by antagonizing leptin and insulin signaling To test this hypothesis, we characterized muscle SOCS3 expression in response to metabolic challenges known to be associated with insulin and/or leptin resistance such as high-fat diet feeding, genetic obesity, lipid infusion, and TNFa injection. We determine the metabolic consequences of transgenic overexpression of SOCS3 exclusively in skeletal muscle of mice, including evaluation of leptin and insulin signaling pathways

Results

Discussion

Materials and Methods