Genet. 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. The transcriptional coactivator peroxisome proliferator-activated receptor (PPAR) coactivator 1 (PGC-1) is usually a key regulator of cellular energy metabolism (40), having known functions in thermogenesis (41), mitochondrial biogenesis (28, 56), fatty acid oxidation (51), and hepatic gluconeogenesis (14, 57). PGC-1 is usually enriched in metabolically active tissues including brown adipose tissue, the heart, and slow-twitch skeletal muscles (30, 41). In contrast to most transcriptional coactivators, expression of the PGC-1 gene is Anethol usually highly inducible in accordance with tissue-specific energy demands. For example, PGC-1 expression is usually rapidly increased in brown adipose tissue following cold exposure (41), in the liver and heart following short-term starvation (28, 57), in skeletal muscle with exercise (2, 12, 38), and in the postnatal heart coincident with an increase in mitochondrial fatty acid oxidation (28). Gain-of-function and loss-of-function studies have exhibited that PGC-1 is necessary and sufficient to increase mitochondrial content and respiratory capacity in response to physiological stimuli in adipocytes (31, 41), skeletal muscle (29, 56), and the heart (1, 29, 44, Rabbit Polyclonal to OR1A1 54). Skeletal-muscle-specific overexpression of PGC-1 results in a fiber type switch from fast-twitch (type II) to slow-twitch (type I) oxidative fibers (30). Slow-twitch fibers are characterized by increased insulin sensitivity, mitochondrial mass, and oxidative capacity. Recent studies have also demonstrated altered expression of PGC-1 in diabetic skeletal muscles (36) and hearts (8). A variety of transcription factors are known to be coactivated by PGC-1, including PPAR (41), PPAR (51), FOXO1 (39), and estrogen-related receptor (ERR) (18, 46). In brown adipose tissue, PGC-1 interacts with PPAR and other transcription factors to regulate the expression of genes involved in adaptive thermogenesis (41). The PGC-1/PPAR pathway is usually involved in the regulation of mitochondrial fatty acid oxidation genes in the heart (28, 51). The PGC-1/FOXO1 pathway activates expression of gluconeogenic genes in the liver (39). More recently, the PGC-1/ERR pathway has been shown to play a role in regulating both fatty acid oxidation and mitochondrial genes in heart and skeletal muscle (20, 35, 45, 53). In contrast to the role of PGC-1 in the regulation of fatty acid oxidation, Anethol mitochondrial respiratory function, and hepatic gluconeogenesis, its function as a potential regulator of glucose utilization pathways has not been well defined. Indeed, the few reports relating PGC-1 to glucose uptake are conflicting. PGC-1 has been reported to induce (33) or repress (34) expression of the glucose transporter GLUT4. Given that regulatory mechanisms exist for reciprocal control of Anethol fatty acid and glucose oxidation, it is likely that this PGC-1 regulatory circuit directly or indirectly influences both pathways. Cellular glucose utilization is usually tightly regulated at multiple levels, including uptake by the glucose transporters (e.g., GLUT4), glycolytic flux, and entry of pyruvate into the Anethol citric acid Anethol cycle via the pyruvate dehydrogenase complex (PDC). In muscle, the PDC serves a critical, rate-limiting step in the regulation of the glucose oxidation pathway by catalyzing the irreversible decarboxylation of pyruvate to acetyl coenzyme A. A significant body of evidence indicates that multiple regulatory pathways converge around the PDC, including allosteric regulation intermediates of fatty acid oxidation and posttranslational control by a family of pyruvate dehydrogenase kinases (PDK1 to -4) and corresponding phosphatases (reviewed in recommendations 13 and 16). The reversible phosphorylation of the PDC inactivates this complex, sparing glucose and favoring fatty acid oxidation. PDK4 has proven to be particularly important in the muscle and liver response to fasting and exercise (15, 37, 54). PDK4 activity and expression are increased in diabetes concurrent with reduced capacity for muscle and hepatic glucose oxidation. Interestingly, PGC-1 is also activated by fasting and exercise. In addition, recent studies have shown that activators of PPAR, a known PGC-1 target, induce the expression of PDK4 (17, 55). However, the mechanism whereby PPAR regulates PDK4 gene expression has not been delineated. Recent studies have also shown that this forkhead transcription factor FOXO1 and the glucocorticoid receptor (GR), two additional potential PGC-1 partners, directly regulate PDK4 expression through consensus binding sites in the PDK4 gene promoter (9, 26). The present study was designed to investigate the potential regulatory influence of the inducible transcriptional coactivator PGC-1 on glucose oxidation through effects on PDK4 gene expression. We found.