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J. Biol. Chem., Vol. 281, Issue 28, 19000-19008, July 14, 2006

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Diminished Hepatic Gluconeogenesis via Defects in Tricarboxylic Acid Cycle Flux in Peroxisome Proliferator-activated Receptor Coactivator-1 (PGC-1)-deficient Mice^*

Shawn C. Burgess¹, Teresa C. Leone, Adam R. Wende, Michelle A. Croce^¶, Zhouji Chen, A. Dean Sherry, Craig R. Malloy, and Brian N. Finck^¶2

From the Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9085, Center for Cardiovascular Research and ^¶Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

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

Received for publication, January 3, 2006 , and in revised form, March 20, 2006.

^* This work supported in part by National Institutes of Health Grants RO1 DK45416, RO1 HL58427, PO1 HL57278, and the Clinical Nutrition Research Unit Core Center (P30 DK56341). The NMR work was supported through the University of Texas Southwestern Mouse Metabolic Phenotyping Center (U24-DK59632) and National Center for Research Resources (RR02584). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material.

¹ Supported by an American Diabetes Association junior faculty award (1-05-JF-05).

² Supported by a NIDDK, National Institutes of Health KO1 award (KO1 DK062903). To whom correspondence should be addressed: Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8031, St. Louis, MO 63110. Tel.: 314-362-8963; Fax: 314-362-8230; E-mail: bfinck{at}im.wustl.edu.

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