Peroxisome proliferator-activated receptors (PPARalpha, -gamma and -delta) are nuclear receptors involved in transcriptional regulations of lipid metabolism. The effect of PPARalpha in regulation of cardiac fatty acid oxidation has been well characterized. Whether PPAR6 also independently regulates fatty acid oxidation in the heart remains unclear. In this study, we tested the hypothesis that PPAR6 activates fatty acids oxidation in cardiomyocytes through transcriptional activation that are independent of PPARalpha. Our results first indicate that PPAR8 abundantly expresses in nucleus of cardiomyocytes. Palmitate oxidation rates were significantly increased in both neonatal and adult cardiornyocytes after treatment of a PPARdelta-selective ligand (GW0742). Further increases of fatty acid oxidation were evident when the treatment was applied to cardiomyocytes overexpressing a wild type PPAR6, but not a mutant PPAR6 that lacks the intact carboxyl ligand-binding domain. Furthermore, genes of fatty acid oxidation enzymes were significantly upregulated in cultured rat neonatal cardiomylocytes when exposed to GW0742. GW0742 can restore partly the expression of certain key genes of fatty acid oxidation in mouse adult cardiornyocytes ioslated from PPARalpha knockout mice. Therefore, while active crosstalk between PPAR6 and -alpha may exist, PPAR6 regulates cardiac fatty acid oxidation in the heart at least partly independent of PPARalpha. We conclude that PPAR6 may play a key role in cardiac energy balance and may serve as a "sensor" of fatty acid of other endogenous ligands in controlling fatty acids oxidation levels in the hearts under normal and pathological conditions. (C) 2003 Elsevier Inc. All rights reserved.