Role of PGC-1α in exercise and fasting-induced adaptations in mouse liver

Haase TN, Ringholm S, Leick L, Bienso RS, Kiilerich K, Johansen S, Nielsen MM, Wojtaszewski JF, Hidalgo J, Pedersen PA, Pilegaard H. Role of PGC-1 alpha in exercise and fasting-induced adaptations in mouse liver. Am J Physiol Regul Integr Comp Physiol 301: R1501-R1509, 2011. First published August 10, 2011; doi:10.1152/ajpregu.00775.2010.-The transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)-1 alpha plays a role in regulation of several metabolic pathways. By use of whole body PGC-1 alpha knockout (KO) mice, we investigated the role of PGC-1 alpha in fasting, acute exercise and exercise training-induced regulation of key proteins in gluconeogenesis and metabolism in the liver. In both wild-type (WT) and PGC-1 alpha KO mice liver, the mRNA content of the gluconeogenic proteins glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) was up-regulated during fasting. Pyruvate carboxylase (PC) remained unchanged after fasting in WT mice, but it was upregulated in PGC-1 alpha KO mice. In response to a single exercise bout, G6Pase mRNA was upregulated in both genotypes, whereas no significant changes were detected in PEPCK or PC mRNA. While G6Pase and PC protein remained unchanged, liver PEPCK protein content was higher in trained than untrained mice of both genotypes. The mRNA content of the mitochondrial proteins cytochrome c (Cyt c) and cytochrome oxidase (COX) subunit I was unchanged in response to fasting. The mRNA and protein content of Cyt c and COXI increased in the liver in response to a single exercise bout and prolonged exercise training, respectively, in WT mice, but not in PGC-1 alpha KO mice. Neither fasting nor exercise affected the mRNA expression of antioxidant enzymes in the liver, and knockout of PGC-1 alpha had no effect. In conclusion, these results suggest that PGC-1 alpha plays a pivotal role in regulation of Cyt c and COXI expression in the liver in response to a single exercise bout and prolonged exercise training, which implies that exercise training-induced improvements in oxidative capacity of the liver is regulated by PGC-1 alpha.