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PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis.

PLoS biology | Apr 11, 2005

http://www.ncbi.nlm.nih.gov/pubmed/15760270

The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) was targeted in mice. PGC-1alpha null (PGC-1alpha(-/-)) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1alpha(-/-) mice. With age, the PGC-1alpha(-/-) mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1alpha(-/-) mice, leading to reduced muscle performance and exercise capacity. PGC-1alpha(-/-) mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1alpha(-/-) mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1alpha(-/-) mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1alpha(-/-) mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1alpha(-/-) mice. These results demonstrate that PGC-1alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

Pubmed ID: 15760270 RIS Download

Mesh terms: Animals | Body Weight | Cerebrovascular Disorders | Exons | Fatty Liver | Female | Insulin Resistance | Male | Mice | Mice, Knockout | Molecular Sequence Data | Muscular Diseases | Obesity | Trans-Activators | Transcription Factors | Transcription, Genetic

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Associated grants

  • Agency: NIA NIH HHS, Id: K08 AG24844
  • Agency: NHLBI NIH HHS, Id: P01 HL57278
  • Agency: NIDDK NIH HHS, Id: P30 DK52574
  • Agency: NIDDK NIH HHS, Id: P30 DK56341
  • Agency: NIDDK NIH HHS, Id: R01 DK45416
  • Agency: NHLBI NIH HHS, Id: R01 HL58427
  • Agency: NHLBI NIH HHS, Id: R01 HL70070

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