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This version published online on October 12, 2006
Endocrinology, doi:10.1210/en.2006-0692
A more recent version of this article appeared on January 1, 2007
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Submitted on May 23, 2006
Accepted on October 5, 2006

INTERLEUKIN-1{beta}-INDUCED INSULIN RESISTANCE IN ADIPOCYTES THROUGH DOWN-REGULATION OF IRS-1 EXPRESSION

Jennifer Jager, Thierry Grémeaux, Mireille Cormont, Yannick Le Marchand-Brustel, and Jean-François Tanti*

INSERM U568, Faculty of Medicine, F-06107 Nice, France; University of Nice Sophia-Antipolis, Nice, France

* To whom correspondence should be addressed. 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 interleukin (IL)-1{beta} amount and metabolic syndrome or type 2 diabetes. However, the ability of IL-1{beta} to alter insulin signaling and action remains to be explored. We demonstrated that IL-1{beta} sligthly increased Glut 1 translocation and basal glucose uptake in 3T3-L1 adipocytes. Importantly, we found that prolonged-IL-1{beta} treatment reduced the insulin-induced glucose uptake whereas an acute treatment had no effect. Chronic treatment with IL-1{beta} 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 IRS-1 but not IRS-2 expression both in 3T3-L1 and human adipocytes. The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and in the alteration of insulin-induced PKB activation and AS160 phosphorylation. Pharmacological inhibition of ERK totally inhibited IL-1{beta}-induced down regulation of IRS-1 mRNA. Moreover, IRS-1 protein expression and insulin-induced PKB activation, AS160 phosphorylation and Glut 4 translocation were partially recovered following treatment with the ERK inhibitor. These results demonstrate that IL-1{beta} 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-1{beta} 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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