Uncoupling protein 3 (UCP3) have an essential role in fatty acid metabolism and mitochondrial redox regulation in skeletal muscle. However, the molecular mechanisms involved in the expression of Ucp3 are poorly known. Here, we show that the PGC-1a/PPARß axis is a crucial mediator of Ucp3 expression in skeletal muscle cells. In silico analysis of the UCP3 promoter and qChIP experiments revealed that the induction of the UCP3 transcript is mediated by the transactivation of a distal PPAR response element (PPRE) at the Ucp3 gene promoter by the coactivator PGC-1a. This mechanism is activated during myogenesis and during metabolic stress induced by fatty acids independently of PGC-1a protein levels. We also provide evidence that Ucp3 is essential for PGC-1a-induced oxidative capacity. Taken together our results highlight PGC-1¿/PPARß as an essential component of the molecular regulation of Ucp3 gene in skeletal muscle cells.

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