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

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

Authors

  • Lin J
  • Wu PH
  • Tarr PT
  • Lindenberg KS
  • St-Pierre J
  • Zhang CY
  • Mootha VK
  • J├Ąger S
  • Vianna CR
  • Reznick RM
  • Cui L
  • Manieri M
  • Donovan MX
  • Wu Z
  • Cooper MP
  • Fan MC
  • Rohas LM
  • Zavacki AM
  • Cinti S
  • Shulman GI
  • Lowell BB
  • Krainc D
  • Spiegelman BM

Journal

Cell

Publication Data

October 1, 2004

Associated Grants

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

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
  • Trans-Activators
  • Transcription Factors
  • Up-Regulation