Disruption of CXC Motif Chemokine Ligand-14 in Mice Ameliorates Obesity-induced Insulin Resistance

Noriko Nara,Yuki Nakayama,Shiki Okamoto,Hiroshi Tamura,Mari Kiyono,Masatoshi Muraoka,Kiyoko Tanaka,Choji Taya,Hiroshi Shitara,Rie Ishii,Hiromichi Yonekawa,Yasuhiko Minokoshi,Takahiko Hara

doi:10.1074/jbc.m700412200

Abstract

In obese individuals, white adipose tissue (WAT) is infiltrated by large numbers of macrophages, resulting in enhanced inflammatory responses that contribute to insulin resistance. Here we show that expression of the CXC motif chemokine ligand-14 (CXCL14), which targets tissue macrophages, is elevated in WAT of obese mice fed a high fat diet (HFD) compared with lean mice fed a regular diet. We found that HFD-fed CXCL14-deficient mice have impaired WAT macrophage mobilization and improved insulin responsiveness. Insulin-stimulated phosphorylation of Akt kinase in skeletal muscle was severely attenuated in HFD-fed CXCL14+/- mice but not in HFD-fed CXCL14-/- mice. The insulin-sensitive phenotype of CXCL14-/- mice after HFD feeding was prominent in female mice but not in male mice. HFD-fed CXCL14-/- mice were protected from hyperglycemia, hyperinsulinemia, and hypoadiponectinemia and did not exhibit increased levels of circulating retinol-binding protein-4 and increased expression of interleukin-6 in WAT. Transgenic overexpression of CXCL14 in skeletal muscle restored obesity-induced insulin resistance in CXCL14-/- mice. CXCL14 attenuated insulin-stimulated glucose uptake in cultured myocytes and to a lesser extent in cultured adipocytes. These results demonstrate that CXCL14 is a critical chemoattractant of WAT macrophages and a novel regulator of glucose metabolism that functions mainly in skeletal muscle.

Highlights

The number of patients suffering from type 2 diabetes is increasing worldwide, due in large part to the increased incidence of obesity
CC motif chemokine ligand-2 (CCL2) directly inhibits insulin-stimulated glucose uptake in cultured adipocytes [12] and myocytes [16] and enhances glucose production in the liver of transgenic mice [14]. These results indicate that the interaction of CCL2 and CCR2 contributes to WAT macrophage infiltration and impaired glucose metabolism in obese mice
Fed mice was infiltrated by a larger number of stromal and vascular cells (SVCs) and macrophages than the WAT of regular diet (RD)-fed mice; all three types of cells in WAT may contribute to the increased level of expression of CXCL14 in WAT of obese mice

Summary

Introduction

The number of patients suffering from type 2 diabetes is increasing worldwide, due in large part to the increased incidence of obesity. In contrast to adipose tissue and skeletal muscle, HFD-induced up-regulation of CXCL14 mRNA was not observed in the livers of CXCL14ϩ/Ϫ mice (supplemental Fig. S3D).

Results

Conclusion