دانلود رایگان مقاله مدلسازی ماتریکس خارج سلولی آدیپوز در مقاومت به انسولین و چاقی

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.

6. Concluding remarks

It is recently ascertained that fibrosis, excess deposition of ECM components, in metabolically active, insulin-sensitive tissues, including the skeletal muscle, adipose tissue and liver has damaging impact on glucose homoeostasis [6,120,121]. Obesogenic ECM remodelling of white adipose tissues is closely linked with the increased levels of circulating ECM proteins and ECM-derived peptides in parallel with increased levels of adipose-derived cytokines. These white adipose tissue-derived ECM or ECM-related molecules may exert metabolically deleterious effects on metabolic crosstalk between the adipose tissue, liver, and skeletal muscles (Fig. 3). Despite a recent implication of ECM-receptor pathway in determining glucose homoeostasis in the skeletal muscle and liver [6], its role in the adipose tissue has not been fully defined. We postulate that the ECM receptor pathway of adipocytes as well as other cell types found in adipose tissues, i.e. inflammatory monocytes and macrophages and vascular endothelial cells are important in transducing intracellular signalling of adipocyte death, angiogenesis, and the infiltration of inflammatory cells, which culminate in insulin resistance. Tissue-specific mouse models that lack a key ECM, ECM modifier, ECM receptor, or intracellular mediator, will help us decipher the importance of the ECM receptor pathway and its regulators in determining metabolic tissue remodelling, function and glucose homoeostasis. We propose the potential of developing therapeutic strategies that target ECM matrix of metabolically active tissues, including the liver, skeletal muscle and the adipose tissue. Current anti- fibrotic drugs being tested in clinical settings have been focused on cancers (e.g. PEGPH20), heart failure (e.g. FT011) and glaucoma surgery (e.g. CLT-28643). The effectiveness of their use in obesity, insulin resistance and type 2 diabetes is unknown and may worth further investigation.