Fatty Acid Homeostasis and Induction of Lipid Regulatory Genes in Skeletal Muscles of Peroxisome Proliferator-activated Receptor (PPAR) α Knock-out Mice EVIDENCE FOR COMPENSATORY REGULATION BY PPARδ

Abstract Ablation of peroxisome proliferator activated receptor (PPAR) α, a lipid-activated transcription factor that regulates expression of β-oxidative genes, results in profound metabolic abnormalities in liver and heart. In the present study we used PPARα knockout (KO) mice to determine whether this transcription factor is essential for regulating fuel metabolism in skeletal muscle. When animals were challenged with exhaustive exercise or starvation, KO mice exhibited lower serum levels of glucose, lactate, and ketones and higher nonesterified fatty acids than wild type (WT) littermates. During exercise, KO mice exhausted earlier than WT and exhibited greater rates of glycogen depletion in liver but not skeletal muscle. Fatty acid oxidative capacity was similar between muscles of WT and KO when animals were fed and only 28% lower in KO muscles when animals were starved. Exercise-induced regulation and starvation-induced regulation of pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, two classical and robustly responsive PPARα target genes, were similar between WT and KO in skeletal muscle but markedly different between genotypes in heart. Real time quantitative PCR analyses showed that unlike in liver and heart, in mouse skeletal muscle PPARδ is severalfold more abundant than either PPARα or PPARγ. In both human and rodent myocytes, the highly selective PPARδ agonist GW742 increased fatty acid oxidation about 2-fold and induced expression of several lipid regulatory genes, including pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, responses that were similar to those elicited by the PPARα agonist GW647. These results show redundancy in the functions of PPARs α and δ as transcriptional regulators of fatty acid homeostasis and suggest that in skeletal muscle high levels of the δ-subtype can compensate for deficiency of PPARα.