Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels

Wen Liu,Ye Yin,Meijing Wang,Ting Fan,Yuyu Zhu,Lihong Shen,Shuang Peng,Jian Gao,Guoliang Deng,Xiangbao Meng,Lingdong Kong,Gen-Sheng Feng,Wenjie Guo,Qiang Xu,Yang Sun

doi:10.1074/jbc.ra119.011840

Abstract

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.

Highlights

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes
When fed an high-fat diet (HFD) for 16 weeks, the cSHP2-KO mice showed considerably less body weight gain than WT counterparts (Fig. 1, A and B), no significant difference was observed in food intake (Fig. 1C)
Results indicated that gluconeogenesis was significantly repressed in cSHP2-KO mice with HFD feeding (Fig. 2C), which was further confirmed by decreased mRNA expression of Pepck and G6Pase in liver (Fig. 2D), suggesting improved hepatic glucose metabolism

Summary

Introduction

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. A interesting finding is that an IL-1b receptor antagonist has shown clinical effectiveness as a treatment for T2D [8, 9] Another cytokine, IL-18, increases in patients with obesity and insulin resistance, and the elevated levels strongly counteract obesity and metabolic syndrome [10,11,12]. Src homology region 2 domain-containing tyrosine phosphatase-2 (SHP2) is a ubiquitously expressed cytoplasmic protein tyrosine phosphatase encoded by the PTPN11 gene in humans [13] This protein is expressed in all insulin-responsive tissues, including muscle [14], liver [15, 16], and adipose [17], as well as in the neurons that control energy regulation [18, 19]. The expression of a dominant-active mutant (SHP2-D61A) in forebrain neurons of female transgenic mice confers resistance to HFD-induced obesity and liver steatosis and is accompanied by improved insulin sensitivity and glucose

Methods

Results

Conclusion