PPARδ Agonism Activates Fatty Acid Oxidation via PGC-1α but Does Not Increase Mitochondrial Gene Expression and Function

PPAR delta (peroxisome proliferator-activated receptor delta) is a regulator of lipid metabolism and has been shown to induce fatty acid oxidation (FAO). PPAR delta transgenic and knock-out mice indicate an involvement of PPAR delta in regulating mitochondrial biogenesis and oxidative capacity; however, the precise mechanisms by which PPAR delta regulates these pathways in skeletal muscle remain unclear. In this study, we determined the effect of selective PPAR delta agonism with the synthetic ligand, GW501516, on FAO and mitochondrial gene expression in vitro and in vivo. Our results show that activation of PPAR delta by GW501516 led to a robust increase in mRNA levels of key lipid metabolism genes. Mitochondrial gene expression and function were not induced under the same conditions. Additionally, the activation of Pdk4 transcription by PPAR delta was coactivated by PGC-1 alpha. PGC-1 alpha, but not PGC-1 beta, was essential for full activation of Cpt-1b and Pdk4 gene expression via PPAR beta agonism. Furthermore, the induction of FAO by PPAR delta agonism was completely abolished in the absence of both PGC-1 alpha and PGC-1 beta Conversely, PGC-1 alpha-driven FAO was independent of PPAR delta. Neither GW501516 treatment nor knockdown of PPAR delta affects PGC-1 alpha-induced mitochondrial gene expression in primary myotubes. These results demonstrate that pharmacological activation of PPAR delta induces FAO via PGC-1 alpha. However, PPAR delta agonism does not induce mitochondrial gene expression and function. PGC-1 alpha-induced FAO and mitochondrial biogenesis appear to be independent of PPAR delta.