The transcriptional coactivator PGC-1 is a key regulator of energy metabolism, yet little is known about its role in control of substrate selection. We found that physiological stimuli known to induce PGC-1 expression in skeletal muscle coordinately upregulate the expression of pyruvate dehydrogenase kinase 4 (PDK4), a negative regulator of glucose oxidation. Forced expression of PGC-1 in C2C12 myotubes induced PDK4 mRNA and protein expression. PGC-1-mediated activation of PDK4 expression was shown to occur at the transcriptional level and was mapped to a putative nuclear receptor binding site. Gel shift assays demonstrated that the PGC-1-responsive element bound the estrogen-related receptor (ERR), a recently identified component of the PGC-1 signa領(lǐng) pathway. In addition, PGC-1 was shown to activate ERR expression. Chromatin immunoprecipitation assays confirmed that PGC-1 and ERR occupied the mPDK4 promoter in C2C12 myotubes. Additionally, transfection studies using ERR-null primary fibroblasts demonstrated that ERR is required for PGC-1-mediated activation of the mPDK4 promoter. As predicted by the effects of PGC-1 on PDK4 gene transcription, overexpression of PGC-1 in C2C12 myotubes decreased glucose oxidation rates. These results identify the PDK4 gene as a new PGC-1/ERR target and suggest a mechanism whereby PGC-1 exerts reciprocal inhibitory influences on glucose catabolism while increasing alternate mitochondrial oxidative pathways in skeletal muscle. TSI激光粒子計數(shù)器/塵埃粒子計數(shù)器/激光塵埃粒子計數(shù)器