Molecular mechanisms of insulin resistance and the role of the adipocyte

Insulin resistance is a common feature of obesity and predisposes the affected individuals to a variety of diseases, including hypertension, dyslipidemias, cardiovascular problems and type 2 diabetes mellitus. However, the molecular mechanisms underlying abnormal insulin action and these other pathological states are not well understood. We have been focusing on cytokines, particularly TNF alpha and fatty acid binding proteins, as potential sites to study the molecular basis of these disorders. The role of TNF alpha in insulin resistance and other pathologies associated with obesity, have been examined in several experimental systems including obese mice with homozygous null mutations at the TNF alpha or TNF receptor loci. Analysis of these animals demonstrated that the genetic absence of TNF signaling in obesity: (i) significantly improves insulin receptor signaling capacity and consequently insulin sensitivity; (ii) prevents brown adipose tissue atrophy and beta (3)-adrenoreceptor deficiency and improves thermo-adaptive responses, (iii) decreases the elevated PAI-1 and TGF beta production; and (iv) lowers hyperlipidemia and hyperleptinemia. Hence, abnormal TNF alpha action in adipocytes disturbs many aspects of metabolic homeostasis in obesity.