Molecular characterization of early adipose tissue fibrosis in the development of diet-induced obesity in mice

Abstract

Obesity harms the health and quality of life of millions of people worldwide and places financial stress on patients and healthcare systems. The metabolic breakdown and development of disease, such as type 2 diabetes, that occurs with obesity has been shown to be largely driven by adipose tissue dysfunction resulting from adipose tissue hypoxia, adipocyte death, macrophage infiltration, and fibrosis. The early stage of adipose tissue fibrosis is poorly understood, particularly in female mice. To identify the initiating molecular changes in adipose tissue fibrosis we have measured the expression of a suite of molecular targets crucial to the development of adipose tissue inflammation and fibrosis in obesity including tumor necrosis factor-alpha (TNF-α; early inflammatory and insulin resistance driver), transforming growth factor-beta (TGF-β; pro-fibrotic cytokine), collagen VI (abundant in fibrotic lesions), matrix metalloproteinase-14 (MMP-14; key extracellular matrix protease in adipose tissue), and tissue inhibitors of MMPs 1-4 (TIMPs 1-4; modulators of proteolytic activity). The first part of this work details the development of a murine model of diet-induced obesity, early insulin resistance, and adipose tissue fibrosis without diagnosable fibrotic build-up quantified with picrosirius red. The second part of this work shows early changes in the expression of key inflammatory and fibrotic components in adipose tissue, including mRNA upregulation of TNF-α, TGF-β, and collagen VI in both sexes, as well as upregulation of TIMP-1 in male mice and TIMP-4 in female mice. Collagen VI immunoreactivity in visceral adipose tissue is also increased, but only in males. These molecular changes are conducive to the development of a fibrotic milieu and represent the initiating steps in adipose tissue fibrosis. This work has improved our understanding of the molecular processes in obesity development and highlights potential targets for therapeutic intervention in the treatment of obesity and metabolic disease.