Peroxisome Proliferator-activated Receptor γ Coactivator 1α (PGC-1α) Promotes Skeletal Muscle Lipid Refueling in Vivo by Activating de Novo Lipogenesis and the Pentose Phosphate Pathway

Exercise induces a pleiotropic adaptive response in skeletal muscle, largely through peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha). PGC-1 alpha enhances lipid oxidation and thereby provides energy for sustained muscle contraction. Its potential implication in promoting muscle refueling remains unresolved, however. Here, we investigated a possible role of elevated PGC-1 alpha levels in skeletal muscle lipogenesis in vivo and the molecular mechanisms that underlie PGC-1 alpha-mediated de novo lipogenesis. To this end, we studied transgenic mice with physiological overexpression of PGC-1 alpha and human muscle biopsies pre-and post-exercise. We demonstrate that PGC-1 alpha enhances lipogenesis in skeletal muscle through liver X receptor alpha-dependent activation of the fatty acid synthase (FAS) promoter and by increasing FAS activity. Using chromatin immunoprecipitation, we establish a direct interaction between PGC-1 alpha and the liver X receptor-responsive element in the FAS promoter. Moreover, we show for the first time that increased glucose uptake and activation of the pentose phosphate pathway provide substrates for RNA synthesis and cofactors for de novo lipogenesis. Similarly, we observed increased lipogenesis and lipid levels in human muscle biopsies that were obtained post-exercise. Our findings suggest that PGC-1 alpha coordinates lipogenesis, intramyocellular lipid accumulation, and substrate oxidation in exercised skeletal muscle in vivo.