en
Scientific article
Open access
English

Hypomorphic mutation of PGC-1beta causes mitochondrial dysfunction and liver insulin resistance

Published inCell metabolism, vol. 4, no. 6, p. 453-464
Publication date2006-12
Abstract

PGC-1beta is a transcriptional coactivator that potently stimulates mitochondrial biogenesis and respiration of cells. Here, we have generated mice lacking exons 3 to 4 of the Pgc-1beta gene (Pgc-1beta(E3,4-/E3,4-) mice). These mice express a mutant protein that has reduced coactivation activity on a subset of transcription factors, including ERRalpha, a major target of PGC-1beta in the induction of mitochondrial gene expression. The mutant mice have reduced expression of OXPHOS genes and mitochondrial dysfunction in liver and skeletal muscle as well as elevated liver triglycerides. Euglycemic-hyperinsulinemic clamp and insulin signaling studies show that PGC-1beta mutant mice have normal skeletal muscle response to insulin but have hepatic insulin resistance. These results demonstrate that PGC-1beta is required for normal expression of OXPHOS genes and mitochondrial function in liver and skeletal muscle. Importantly, these abnormalities do not cause insulin resistance in skeletal muscle but cause substantially reduced insulin action in the liver.

eng
Keywords
  • Animals
  • Gene Expression Regulation / drug effects
  • Glucose Clamp Technique
  • Hypoglycemic Agents / pharmacology
  • Insulin / pharmacology
  • Insulin Resistance / genetics
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Mice, Knockout
  • Mitochondria, Liver / genetics
  • Mitochondria, Liver / metabolism
  • Mitochondria, Liver / pathology
  • Mitochondria, Muscle / genetics
  • Mitochondria, Muscle / metabolism
  • Mitochondria, Muscle / pathology
  • Mitochondrial Proteins / biosynthesis
  • Mitochondrial Proteins / genetics
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Mutation
  • Organ Specificity
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Trans-Activators / deficiency
  • Trans-Activators / metabolism
  • Transcription Factors
Affiliation Not a UNIGE publication
Citation (ISO format)
VIANNA, Claudia R et al. Hypomorphic mutation of PGC-1beta causes mitochondrial dysfunction and liver insulin resistance. In: Cell metabolism, 2006, vol. 4, n° 6, p. 453–464. doi: 10.1016/j.cmet.2006.11.003
Main files (1)
Article (Published version)
accessLevelPublic
Identifiers
ISSN of the journal1550-4131
34views
6downloads

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