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

Cell | Oct 1, 2004

PGC-1alpha 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-1alpha 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/EBPbeta is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1alpha-independent manner. Despite having reduced mitochondrial function, PGC-1alpha 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-1alpha in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.

Pubmed ID: 15454086 RIS Download

Mesh terms: Adaptation, Physiological | Animals | Appetite Regulation | Basal Ganglia Diseases | Brain | CCAAT-Enhancer-Binding Protein-beta | Corpus Striatum | Energy Metabolism | Gene Expression Regulation | Gluconeogenesis | Glucose | Hepatocytes | Homeostasis | Hyperkinesis | Liver | Mice | Mice, Knockout | Mitochondria | Neurodegenerative Diseases | Neurons | Obesity | Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha | Trans-Activators | Transcription Factors | Up-Regulation

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Associated grants

  • Agency: NIDDK NIH HHS, Id: DK61562
  • Agency: NIDDK NIH HHS, Id: R01 DK040936
  • Agency: NINDS NIH HHS, Id: NS002174
  • Agency: NIDDK NIH HHS, Id: DK40936
  • Agency: NIDDK NIH HHS, Id: DK065584
  • Agency: NINDS NIH HHS, Id: NS045242
  • Agency: NIDDK NIH HHS, Id: DK54477

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