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J. Biol. Chem., Vol. 280, Issue 14, 14222-14229, April 8, 2005

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FoxO1 Stimulates Fatty Acid Uptake and Oxidation in Muscle Cells through CD36-dependent and -independent Mechanisms^*

Claire C. Bastie, Zaher Nahlé, Thomas McLoughlin¶, Karyn Esser||, Wenwei Zhang**, Terry Unterman**, and Nada A. Abumrad

From the Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York 11794-8661, Department of Medicine, Division of Nutritional Science, Washington University, St. Louis, Missouri 63110, ^||Department of Physiology, University of Kentucky, Lexington, Kentucky 40536, ^¶Department of Kinesiology, University of Toledo, Toledo, Ohio 43606, and Departments of ^**Medicine and Physiology and Biophysics, University of Illinois at Chicago and Jesse Brown VA Medical Center, Chicago, Illinois 60612

Emerging evidence documents a key function for the forkhead transcription factor FoxO1 in cellular metabolism. Here, we investigate the role of FoxO1 in the regulation of fatty acid (FA) metabolism in muscle cells. C2C12 cells expressing an inducible construct with either wild type FoxO1 or a mutant form (FoxO1/TSS) refractory to the protein kinase B inhibitory effects were generated. FoxO1 activation after myotube formation altered the expression of several genes of FA metabolism. Acyl-CoA oxidase and peroxisome proliferator-activated receptor mRNA levels increased 2.2-fold and 1.4-fold, respectively, whereas mRNA for acetyl-CoA carboxylase decreased by 50%. Membrane uptake of oleate increased 3-fold, and oleate oxidation increased 2-fold. Cellular triglyceride content was also increased. The enhanced FA utilization induced by FoxO1 was mediated by a severalfold increase in plasma membrane level of the fatty acid translocase FAT/CD36 and eliminated by cell treatment with the CD36 inhibitor sulfo-N-succinimidyl-oleate. We conclude that FoxO1 activation induces coordinate increases in FA uptake and oxidation and that these effects are mediated, at least in part, by membrane enrichment in CD36. The data suggest that FoxO1 contributes to preparing the muscle cell for the increased reliance on FA metabolism that is characteristic of fasting. Dysregulation of FoxO1 in muscle could contribute to intramuscular lipid accumulation and insulin resistance by maintaining activation of FA uptake.

Received for publication, December 3, 2004 , and in revised form, January 28, 2005.

^* This work was supported by National Institutes of Health Grants DK33301 (to N. A. A.), DK600022 (to N. A. A.), AR445617 (to K. E.), and DK41430 (to T. U.); a grant from Philip Morris USA (to N. A. A. and Z. N.); and a VA Merit Award (to T. U.). 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: Dept. of Medicine, Division of Nutritional Science, Washington University, Campus Box 8031, St. Louis, MO 63110. Tel.: 314-747-0348; Fax: 314-362-8529; E-mail: nabumrad{at}wustl.edu.

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