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J. Biol. Chem., Vol. 283, Issue 21, 14317-14326, May 23, 2008

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CD36-dependent Regulation of Muscle FoxO1 and PDK4 in the PPAR/β-mediated Adaptation to Metabolic Stress^*

Zaher Nahlé¹, Michael Hsieh, Terri Pietka, Chris T. Coburn, Paul A. Grimaldi^¶, Michael Q. Zhang^||, Debopriya Das^**, and Nada A. Abumrad

From the Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, the Department of Biology, Western Carolina University, Cullowhee, North Carolina 28723, ^¶Inserm U636, Université de Nice-Sophia Antipolis, Centre de Biochimie, Parc Valrose, UFR Sciences, Nice F-06108, France, ^||Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, and the ^**Life Sciences Division, Ernest O. Lawrence Berkeley National Laboratory, Berkeley, California 94270

The transcription factor FoxO1 contributes to the metabolic adaptation to fasting by suppressing muscle oxidation of glucose, sparing it for glucose-dependent tissues. Previously, we reported that FoxO1 activation in C₂C₁₂ muscle cells recruits the fatty acid translocase CD36 to the plasma membrane and increases fatty acid uptake and oxidation. This, together with FoxO1 induction of lipoprotein lipase, would promote the reliance on fatty acid utilization characteristic of the fasted muscle. Here, we show that CD36-mediated fatty acid uptake, in turn, up-regulates protein levels and activity of FoxO1 as well as its target PDK4, the negative regulator of glucose oxidation. Increased fatty acid flux or enforced CD36 expression in C₂C₁₂ cells is sufficient to induce FoxO1 and PDK4, whereas CD36 knockdown has opposite effects. In vivo, CD36 loss blunts fasting induction of FoxO1 and PDK4 and the associated suppression of glucose oxidation. Importantly, CD36-dependent regulation of FoxO1 is mediated by the nuclear receptor PPAR/β. Loss of PPAR/β phenocopies CD36 deficiency in blunting fasting induction of muscle FoxO1 and PDK4 in vivo. Expression of PPAR/β in C₂C₁₂ cells, like that of CD36, robustly induces FoxO1 and suppresses glucose oxidation, whereas co-expression of a dominant negative PPAR/β compromises FoxO1 induction. Finally, several PPRE sites were identified in the FoxO1 promoter, which was responsive to PPAR/β. Agonists of PPAR/β were sufficient to confer responsiveness and transactivate the heterologous FoxO1 promoter but not in the presence of dominant negative PPAR/β. Taken together, our findings suggest that CD36-dependent FA activation of PPAR/β results in the transcriptional regulation of FoxO1 as well as PDK4, recently shown to be a direct PPAR/β target. FoxO1 in turn can regulate CD36, lipoprotein lipase, and PDK4, reinforcing the action of PPAR/β to increase muscle reliance on FA. The findings could have implications in the chronic abnormalities of fatty acid metabolism associated with obesity and diabetes.

Received for publication, August 6, 2007 , and in revised form, February 21, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant DK33301 (to N. A.). This work was also supported by an American Heart Association grant-in-aid award (to Z. N.), a grant from the Phillip Morris External Research Program (to N. A. and Z. N.), and Clinical Nutrition Research Unit Grant DK56351. 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: Campus Box 8031, Washington University School of Medicine, St Louis, MO 63110. E-mail: znahle{at}im.wustl.edu.

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