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J. Biol. Chem., Vol. 282, Issue 13, 9430-9435, March 30, 2007

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Insulin Antagonizes Interleukin-6 Signaling and Is Anti-inflammatory in 3T3-L1 Adipocytes^*

From the Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at Göteborg University, SE-413 45 Göteborg, Sweden

Adipose tissue secretes different adipokines, including interleukin-6 (IL-6), that have been implicated in the insulin resistance and inflammatory state characterizing obesity. We examined the putative cross-talk between insulin and IL-6 in adipose cells and found that insulin exerts an inhibitory effect on the IL-6 signaling pathway by altering the post-translational modifications of the signal transducer and activator of transcription 3 (STAT3). Insulin reduces the tyrosine phosphorylation and increases the serine phosphorylation of STAT3, thereby reducing its nuclear localization and transcriptional activity. Signaling through the MEK/MAPK pathway plays an important role as treatment with the MEK inhibitor PD98059 reduces the effects of insulin on IL-6 signaling. We also show that the protein tyrosine phosphatase SHP2 is activated upon insulin signaling and is required for the dephosphorylation of STAT3 and that insulin exerts a synergistic effect with IL-6 on suppressor of cytokine signaling 3 expression. As a consequence, the IL-6-induced expression of the inflammatory markers serum amyloid A 3 and haptoglobin are significantly decreased in cells incubated with both IL-6 and insulin. Thus, insulin exerts an important anti-inflammatory effect in adipose cells by impairing the IL-6 signal at several levels.

Received for publication, October 24, 2006 , and in revised form, January 9, 2007.

^* This work was supported by grants from the Swedish Research Council (K2004-72X-03506-33A), the Novo Nordisk Foundation, the Martina and Wilhelm Lundgren Foundation, the Inger Hultman Foundation, the Swedish Diabetes Association, and the Torsten and Ragnar Söderberg Foundation. It was also a part of the project "Hepatic and Adipose Tissue and Functions in the Metabolic Syndrome" (HEPADIP, see www.hepadip.org/), which is supported by the European Commission as an Integrated Project under the 6th Framework Programme (Contract LSHM-CT-2005-018734). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 46-31-3421104; Fax: 46-31-829138; E-mail: ulf.smith{at}medic.gu.se.

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