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Papers In Press, published online ahead of print May 2, 2006
J. Biol. Chem, 10.1074/jbc.M600050200
Submitted on January 3, 2006
Accepted on May 2, 2006

Diminished hepatic gluconeogenesis via defects in TCA cycle flux in ppargamma coactivator-1alpha (PGC-1alpha )-deficient mice

Shawn C. Burgess, Teresa C. Leone, Adam R. Wende, Michelle A. Croce, Zhouji Chen, A. Dean Sherry, Craig R. Malloy, and Brian N. Finck

Gerontology and Nutritional Sciences, Washington University School of Medicine, Saint Louis, MO 63110

Corresponding Author: bfinck{at}im.wustl.edu

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


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