Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes

Abstract

Insulin resistance due to obesity is a primary event in the development of type 2 diabetes. Recent work indicates a central role of adipose tissue dysfunction in linking obesity to insulin resistance. Fatty acids and their derivatives are mediators of insulin resistance in skeletal muscle, probably through deleterious effects on the insulin signalling pathway. Increased exposure of skeletal muscle tissue to elevated fatty acids in rodents and humans impairs insulin-stimulated glucose uptake. The impaired ability of adipose tissue to sequester fatty acids in triglyceride stores results in increasing fatty acid concentrations in the circulation and the exposure of skeletal muscle to these high fatty acid levels. This impairment of adipose function can be caused by a chronic inflammatory state that arises within adipose tissue in obese animals and humans. Inflammatory cytokines, including tumour-necrosis factor-α (TNFα), have profound effects on adipocyte metabolism by impairing triglyceride synthesis and storage, and promoting the hydrolysis and release of triglycerides as free fatty acids. These effects are mediated in part through downregulation of the key adipocyte transcription factor PPARγ (peroxisome proliferator-activated receptor-γ). Recent data implicate lipid-droplet proteins, including newly described CIDE family proteins, in the promotion of triglyceride storage and as significant targets of PPARγ regulation. Through effects on these proteins, downregulation of PPARγ can mediate diminished lipid storage ability of inflamed adipose tissue. Expression of these proteins may be determinants of the differential ability to sequester fat away from the circulation and the propensity of obese humans to develop insulin resistance.