Absence of the proteoglycan decorin reduces glucose tolerance in overfed male mice

Jessica Svärd,Christine Haugen,Anne E Mellgren,Jørn V Sagen,Camilla E N Sommervoll,Simon N Dankel,Oddrun A Gudbrandsen,Therese H Røst,Johan Fernø,Eyvind Rødahl,Gunnar Mellgren

doi:10.1038/s41598-018-37501-x

Abstract

Studies have implicated the extracellular matrix (ECM) of adipose tissue in insulin resistance. The proteoglycan decorin, a component of ECM, has been associated with glucose tolerance, but possible causal effects on metabolism remain to be explored. We here sought to determine metabolic consequences of loss of decorin in mice (DcnKO). DcnKO mice were fed a low-fat (LF) or high-fat (HF) diet for 10 weeks and body weight and food intake was recorded. An intraperitoneal glucose tolerance test was performed after eight weeks. Blood samples and adipose, liver and muscle tissues were collected at sacrifice. Global gene expression was measured in adipose tissue, and expression of decorin was also analyzed in human adipose samples. DcnKO mice showed increased feed efficiency during overfeeding and impaired glucose tolerance. Adipose leptin mRNA and circulating leptin levels were elevated in DcnKO mice, along with a downregulation of genes involved in ECM organization and triglyceride biosynthesis, and an upregulation of adipose genes involved in complement and coagulation cascades. Consistent with a protective metabolic role for decorin, in obese patients we found increased adipose decorin expression after profound fat loss, particularly in the stromal vascular fraction. Loss of decorin in mice caused impaired glucose tolerance in association with increased feed efficiency and altered gene expression in adipose tissue. Our data provide evidence that decorin is an important factor for maintaining glucose tolerance.

Highlights

Obesity has become more prevalent during the last decades, and it is associated with metabolic disturbances which can be related to structural changes in tissues and cross-talk between different organs
As expected we found that high-fat (HF) feeding increased Dcn mRNA in epididymal white adipose tissue (Fig. 1A)
We found increased expression of Dcn in inguinal white adipose tissue, brown adipose tissue (BAT), and skeletal muscle, whereas there was no difference in the hepatic gene expression (Fig. 1A)

Summary

Introduction

Obesity has become more prevalent during the last decades, and it is associated with metabolic disturbances which can be related to structural changes in tissues and cross-talk between different organs. Decorin interacts with several molecules present in the ECM, including structural proteins such as types VI, XII and XIV collagen, fibronectin and elastin[20,21,22,23,24], and growth factors such as EGF, TGFβ, TNFα and myostatin[25,26,27,28] These interactions may, in addition to stabilizing the extracellular matrix, participate in regulating the metabolism[29] and activity of these growth factors at its receptors. These findings indicate that decorin may play an important role in adipose tissue function and in the pathophysiology of obesity. We used the well-established C57BL/6 mouse model for obesity and impaired glucose tolerance and type 2 diabetes[30], to test a possible causal impact of decorin on body weight, glucose tolerance and adipose tissue in high-fat challenged Dcn null (dcnKO) C57BL/6J mice

Methods

Results

Conclusion