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Interleukin-1ß-Induced Insulin Resistance in Adipocytes through Down-Regulation of Insulin Receptor Substrate-1 Expression

Institut National de la Santé et de la Recherche Médicale (INSERM) U568, Faculty of Medicine, F-06107 Nice, France; and Université de Nice Sophia-Antipolis, UFR Sciences, F-06002 Nice, France

Address all correspondence and requests for reprints to: Jean-François Tanti, Institut National de la Santé et de la Recherche Médicale U 568, Faculty of Medicine, Avenue de Valombrose, 06107 Nice Cedex 2, France. E-mail: tanti{at}unice.fr.

Inflammation is associated with obesity and insulin resistance. Proinflammatory cytokines produced by adipose tissue in obesity could alter insulin signaling and action. Recent studies have shown a relationship between IL-1ß level and metabolic syndrome or type 2 diabetes. However, the ability of IL-1ß to alter insulin signaling and action remains to be explored. We demonstrated that IL-1ß slightly increased Glut 1 translocation and basal glucose uptake in 3T3-L1 adipocytes. Importantly, we found that prolonged IL-1ß treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. Chronic treatment with IL-1ß slightly decreased the expression of Glut 4 and markedly inhibited its translocation to the plasma membrane in response to insulin. This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. Pharmacological inhibition of ERK totally inhibited IL-1ß-induced down-regulation of IRS-1 mRNA. Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. These results demonstrate that IL-1ß reduces IRS-1 expression at a transcriptional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activation. By targeting IRS-1, IL-1ß is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes.

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