Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice

Jiandie Lin, Pei Hsuan Wu, Paul T. Tarr, Katrin S. Lindenberg, Julie St-Pierre, Chen Yu Zhang, Vamsi K. Mootha, Sibylle Jäger, Claudia R. Vianna, Richard M. Reznick, Libin Cui, Monia Manieri, Mi X. Donovan, Zhidan Wu, Marcus P. Cooper, Melina C. Fan, Lindsay M. Rohas, Ann Marie Zavacki, Saverio Cinti, Gerald I. ShulmanBradford B. Lowell, Dimitri Krainc, Bruce M. Spiegelman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

915 Scopus citations


PGC-1α is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1α are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPβ is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1α-independent manner. Despite having reduced mitochondrial function, PGC-1α null mice are paradoxically lean and resistant to diet-induced obesity. This is largely due to a profound hyperactivity displayed by the null animals and is associated with lesions in the striatal region of the brain that controls movement. These data illustrate a central role for PGC-1α in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.

Original languageEnglish (US)
Pages (from-to)121-135
Number of pages15
Issue number1
StatePublished - Oct 1 2004

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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