Muscle tissue is the major site for insulin-stimulated glucose uptake in vivo, due primarily to the recruitment of the insulinsensitive glucose transporter (GLUT4) to the plasma membrane. Surprisingly, virtually all cultured muscle cells express little or no GLUT4. We show here that adenovirus-mediated expression of the transcriptional coactivator PGC-1, which is expressed in muscle in vivo but is also deficient in cultured muscle cells, causes the total restoration of GLUT4 mRNA levels to those observed in vivo. This increased GLUT4 expression correlates with a 3-fold increase in glucose transport, although much of this protein is transported to the plasma membrane even in the absence of insulin. PGC-1 mediates this increased GLUT4 expression, in large part, by binding to and coactivating the muscle-selective transcription factor MEF2C. These data indicate that PGC-1 is a coactivator of MEF2C and can control the level of endogenous GLUT4 gene expression in muscle.MEF2 ͉ diabetes T ype 2 diabetes mellitus, the most common endocrine disorder, potentially affects up to 5% of the western population (1). Patients with type 2 diabetes generally suffer both from reduced insulin secretion and from resistance to the actions of insulin. Hyperglycemic-hyperinsulinemic clamp analyses of human type 2 diabetic patients show that insulin resistance in muscle is caused by a defect in glucose transport (2). The principal insulin-sensitive glucose transporter in muscle is the insulin-sensitive glucose transporter (GLUT4), which is recruited to the sarcolemma following insulin stimulation. Definitive evidence that GLUT4 is the primary mediator both of basal and insulin-stimulated glucose transport in muscle comes from muscle-specific GLUT4 knockout mice (3). Ex vivo glucose transport assays of isolated muscle tissue from these mice demonstrate an 80% reduction in basal glucose transport and a complete loss of insulin-stimulated glucose uptake. Overexpression of GLUT4 in muscle of genetically diabetic mice (db͞db) alleviates insulin resistance and improves glycemic control by elevating both basal and insulin-stimulated glucose transport (4). Together, these data point to skeletal muscle glucose transport as the rate-limiting step for whole body glucose disposal and suggest that the regulation of GLUT4 expression is a potential target for treatment of diabetes mellitus.We have previously described a coactivator of PPAR␥ and other nuclear receptors termed PGC-1 that plays a key role in several aspects of thermogenesis and oxidative metabolism. PGC-1 also stimulates mitochondrial biogenesis per se through coactivation of nuclear respiratory factor-1 (NRF-1) (5, 6). Indeed, PGC-1 expression in both muscle and fat cells activates the expression of several genes of the oxidative phosphorylation pathway, including cytochrome c oxidase (COX) subunits II and IV, and ATP synthetase. This coactivator also stimulates the induction of a mitochondrial uncoupling protein (UCP), UCP-1 in fat cells and UCP-2 in muscle cells (6).The chronically inc...
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