Pathogenic role of inflammatory cytokines in obesity: from insulin resistance to diabetes mellitus.

It is now well established that an inflammatory component contributes to the pathogenesis of obesity-linked diabetes and cardiovascular diseases. First proposed by Hotamisligil et al. [1] more than a decade ago, there is now convincing experimental evidence for the existence of an inflammatory link between obesity and the occurrence of the insulin resistance dyslipidemic syndrome commonly known as the ‘metabolic syndrome’. Indeed, several molecules that are best known for their role in immune and inflammatory cells are now considered as key modulators of energy metabolism in insulin target tissues and are secreted by fat cells in the expanded adipose tissue of obese subjects. These include proinflammatory cytokines, e.g. tumor necrosis factor(TNF ), interleukin (IL)-6, IL-1, and interferon, as well as adipose-specific cytokines or ‘adipokines’ such as leptin and resistin. These inflammatory mediators exert their actions via a complex interplay of signal transduction mechanisms that we are just beginning to fully appreciate. Several molecular targets have been proposed to mediate the insulin-resistant effects of cytokines in insulin target tissues. The principal goal of this chapter is to briefly review current knowledge on the mechanisms by which cytokines promote insulin resistance in obesity. Particular emphasis will be placed on inducible nitric oxide (NO) synthase (iNOS), an inducible isoform of the NO synthase (NOS) family that is overexpressed in the skeletal muscle and adipose tissues of several animal models of obesity. Allison SP, Go VLW (eds): Metabolic Issues of Clinical Nutrition. Nestlé Nutrition Workshop Series Clinical & Performance Program, vol 9, pp 141–153, Nestec Ltd., Vevey/S. Karger AG, Basel, © 2004.