Role of Adipocyte Products and Inflammation

Increased levels of NEFA and inflammatory cytokines (e.g., tumor necrosis factor a [TNFa] and interleukin 6 [IL-6]) released by expanded visceral adipose tissue adversely influence the insulin signaling cascade (19,20). NEFA inhibit insulin-stimulated glucose metabolism in skeletal muscle and suppress glycogenolysis in liver (21,22). NEFA activate cellular kinases, including atypical protein kinase C isoforms by increasing cellular diacylglycerol levels, which can activate the inflammatory kinases inhibitor kB kinase (IKK) and JNK, increasing serine/ threonine phosphorylation of IRS-1 and reducing downstream IRS-1 signaling, as described above (23-25). TNFa enhances adipocyte lipolysis, which further increased NEFA levels, and also elicits its own direct negative effects on insulin signaling pathways (26). Neutralization of TNFa dramatically reverses insulin resistance in rodent models; however, the magnitude of its involvement in human insulin resistance is not entirely clear (27). The proinflammatory IL-6 inhibits the insulin signal by augmenting the expression of SOCS proteins (28,29).

While circulating NEFA and several adipokines are increased in visceral obesity, the levels of the adipose-specific protein adiponectin are decreased, reducing its insulin-sensitizing effects in liver and muscle (19,30). Adiponectin signals via AMP kinase, a stress-activated signaling enzyme implicated in a variety of metabolic responses, including suppression of hepatic gluconeogenesis, glucose uptake in exercising skeletal muscle, fatty acid oxidation, and inhibition of lipolysis, which may explain its beneficial metabolic effects (30-34).

A close connection between insulin resistance and classical inflammatory signaling pathways has also been recently identified. NF-kB is held in an inactive state in resting conditions by binding to an inhibitory partner, IkB (35). Phosphorylation of IkB by its kinase (IKK) leads to I B degradation, releasing NF-kB for translocation to the nucleus where it can influence the transcription of diverse genes involved in the inflammatory response. High doses of salicylates, which block IKK activity (36) can ameliorate hyperglycemia and insulin resistance in diabetes and obesity (37,38). More importantly, genetic disruption of IKKp-normalized skeletal insulin resistance caused by NEFA via improvement in IRS-1 tyrosine phosphorylation and activation of its downstream signal cascade (39). Overall, this line of evidence suggests that IKK may be an important target for the development of new therapeutics in insulin resistance, especially in the setting of visceral adiposity.

In addition to their effects on insulin signaling, the circulating adipose tissue factors strongly influence vascular endothelial function, linking the increased vascular risk in the metabolic syndrome with mechanisms of cellular insulin resistance (30,40). Adipose secretory factors also recruit and activate inflammatory cells, which can further perpetuate a systemic inflammatory milieu that can strongly influence vascular function and atherogenesis (41).

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