Diminished hepatic gluconeogenesis via defects in tricarboxylic acid cycle flux in peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-deficient mice

The peroxisome proliferator-activated receptor gamma(PPAR gamma) coactivator 1 alpha(PGC-1 alpha) is a highly inducible transcriptional coactivator implicated in the coordinate regulation of genes encoding enzymes involved in hepatic fatty acid oxidation, oxidative phosphorylation, and gluconeogenesis. The present study sought to assess the effects of chronic PGC-1 alpha deficiency on metabolic flux through the hepatic gluconeogenic, fatty acid oxidation, and tricarboxylic acid cycle pathways. To this end, hepatic metabolism was assessed in wild-type (WT) and PGC-1 alpha(-/-) mice using isotopomer-based NMR with complementary gene expression analyses. Hepatic glucose production was diminished in PGC-1 alpha(-/-) livers coincident with reduced gluconeogenic flux from phosphoenolpyruvate. Surprisingly, the expression of PGC-1 alpha target genes involved in gluconeogenesis was unaltered in PGC-1 alpha(-/-) compared withWTmice under fed and fasted conditions. Flux through tricarboxylic acid cycle and mitochondrial fatty acid beta-oxidation pathways was also diminished in PGC-1 alpha-/- livers. The expression of multiple genes encoding tricarboxylic acid cycle and oxidative phosphorylation enzymes was significantly depressed in PGC-1 alpha(-/-) mice and was activated by PGC-1 alpha overexpression in the livers of WT mice. Collectively, these findings suggest that chronic wholeanimal PGC-1 alpha deficiency results in defects in hepatic glucose production that are secondary to diminished fatty acid beta-oxidation and tricarboxylic acid cycle flux rather than abnormalities in gluconeogenic enzyme gene expression per se.