Adipose extracellular matrix remodelling in obesity and insulin resistance

Abstract

The extracellular matrix (ECM) of adipose tissues undergoes constant remodelling to allow adipocytes and their precursor cells to change cell shape and function in adaptation to nutritional cues. Abnormal accumulation of ECM components and their modifiers in adipose tissues has been recently demonstrated to cause obesity-associated insulin resistance, a hallmark of type 2 diabetes. Integrins and other ECM receptors (e.g. CD44) that are expressed in adipose tissues have been shown to regulate insulin sensitivity. It is well understood that a hypoxic response is observed in adipose tissue expansion during obesity progression and that hypoxic response accelerates fibrosis and inflammation in white adipose tissues. The expansion of adipose tissues should require angiogenesis; however, the excess deposition of ECM limits the angiogenic response of white adipose tissues in obesity. While recent studies have focused on the metabolic consequences and the mechanisms of adipose tissue expansion and remodelling, little attention has been paid to the role played by the interaction between peri-adipocyte ECM and their cognate cell surface receptors. This review will address what is currently known about the roles played by adipose ECM, their modifiers, and ECM receptors in obesity and insulin resistance. Understanding how excess ECM deposition in the adipose tissue deteriorates insulin sensitivity would provide us hints to develop a new therapeutic strategy for the treatment of insulin resistance and type 2 diabetes.

Keywords: Adipose tissue; Extracellular matrix; Fibrosis; Insulin resistance; Integrins.

Fig. 1

Adipose tissue remodelling during the development of obesity. Adipose tissues undergo dramatic remodelling during the development of obesity. These include enlargement of adipocytes, accumulation of extracellular matrix components, increased formation of new blood vessels and increased perfusion of capillaries, and increased infiltration of pro-inflammatory macrophages (M1-like).

Fig. 2

Proposed model for how the activation of ECM receptor pathway in the adipose tissue is linked to obesity-associated insulin resistance. It is proposed that activation of ECM-receptor pathway would induce the expression of genes that mediate the metabolically unfavourable processes, including adipocyte death, inhibition of angiogenesis and attraction of pro-inflammatory macrophage infiltration which culminate in insulin resistance. Potential downstream intracellular signalling partners of each ECM receptor include FAK for integrin receptors [119], ERM for CD44 receptor [85] and MAPKs for CD36 receptor [122]. ECM: extracellular matrix; FAK: focal adhesion kinase; ERM: ezrin–radixin–moesin; MAPKs: mitogen-activated protein kinases; VEGF: vascular endothelial growth factor; ATM: adipose tissue macrophage.

Fig. 3

Fibrotic and inflammatory white adipose tissue remodelling in crosstalk with the liver and skeletal muscles. Fibrotic and inflammatory adipose tissue remodelling is associated with the increased circulating levels of THBS1, OPN, endotrophin in parallel with IL6 and TNFα. These circulating factors derived from expanding adipose tissues induce insulin resistance of the liver and skeletal muscles.