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J. Biol. Chem., Vol. 279, Issue 40, 41294-41301, October 1, 2004

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Fatty Acid-induced Insulin Resistance in L6 Myotubes Is Prevented by Inhibition of Activation and Nuclear Localization of Nuclear Factor B^*

Sandeep Sinha, German Perdomo, Nicholas F. Brown, and Robert M. O'Doherty¶

From the Departments of Medicine and Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Recent studies have implicated inhibitor of B kinase (IKK) in mediating fatty acid (FA)-induced insulin resistance. How IKK causes these effects is unknown. The present study addressed the role of nuclear factor B (NFB), the distal target of IKK activity, in FA-induced insulin resistance in L6 myotubes, an in vitro skeletal muscle model. A 6-h exposure of myotubes to the saturated FA palmitate reduced insulin-stimulated glucose uptake by 30%, phosphatidylinositol-3 kinase and protein kinase B phosphorylation by 40%, and stimulated inhibitor of B degradation and the nuclear translocation of NFB. On the other hand, the -3 polyunsaturated FA linolenate neither induced insulin resistance nor promoted nuclear localization of NFB. Supporting the hypothesis that IKK acts through NFB to cause insulin resistance, the IKK inhibitors acetylsalicylate and parthenolide prevented FA-induced reductions in insulin-stimulated glucose uptake and NFB nuclear translocation. Most importantly, NFB SN50, a cell-permeable peptide that inhibits NFB nuclear translocation downstream of IKK, was sufficient to prevent palmitate-induced reductions in insulin-stimulated glucose uptake. Acetylsalicylate, but not NFB SN50, prevented FA effects on phosphatidylinositol-3 kinase activity and protein kinase B phosphorylation. We conclude that FAs induce insulin resistance and activates NFB in L6 cells. Furthermore, inhibition of NFB activation, indirectly by preventing IKK activation or directly by inhibiting NFB nuclear translocation, prevents the detrimental effects of palmitate on the metabolic actions of insulin in L6 myotubes.

Received for publication, June 11, 2004

^* This work was supported in part by an American Diabetes Association Career Development Award and national Institutes of Health Grant R01-DK58855-01 (both to R. M. O.) and an American Diabetes Association Faculty Award (to N. F. B). 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.

^¶ To whom correspondence should be addressed: E1112 Biomedical Science Tower, Pittsburgh, PA 15261. Tel.: 412-624-8535; Fax: 412-648-3290; E-mail: odohertyr{at}msx.dept-med.pitt.edu.

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