Abstract
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 delta 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.
Highlights
Maintaining the appropriate balance between glucose and fatty acid (FA)1 metabolism is essential for muscle cells as they undergo nutritional transitions from feeding to fasting
Our findings indicate that activation of FoxO1 contributes to the adaptive response of muscle during the transition from feeding to fasting
Insulin signaling declines, and FoxO1 is transported to the nucleus, where it can affect the transcription of target genes
Summary
Vol 280, No 14, Issue of April 8, pp. 14222–14229, 2005 Printed in U.S.A. FoxO1 Stimulates Fatty Acid Uptake and Oxidation in Muscle Cells through CD36-dependent and -independent Mechanisms*. 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. FoxO1 expression is increased with fasting [7], which induces the key regulatory enzyme pyruvate dehydrogenase kinase (PDK) 4 [8], a FoxO1 target gene. Recent studies with mice overexpressing a dominant negative insulin-like growth factor I receptor in muscle documented low FA oxidation levels in this tissue that were reversed by muscle-targeted overexpression of CD36 [14] This suggested that the insulin-like growth factor I pathway, possibly via its regulation of FoxO protein activation, modulates FA metabolism. Our results indicate that FoxO1 increases FA uptake and oxidation in muscle cells by increasing membrane CD36 content and by regulating expression of key genes of FA utilization
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