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Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma.

Calorie restriction extends lifespan in organisms ranging from yeast to mammals. In yeast, the SIR2 gene mediates the life-extending effects of calorie restriction. Here we show that the mammalian SIR2 orthologue, Sirt1 (sirtuin 1), activates a critical component of calorie restriction in mammals; that is, fat mobilization in white adipocytes. Upon food withdrawal Sirt1 protein binds to and represses genes controlled by the fat regulator PPAR-gamma (peroxisome proliferator-activated receptor-gamma), including genes mediating fat storage. Sirt1 represses PPAR-gamma by docking with its cofactors NCoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors). Mobilization of fatty acids from white adipocytes upon fasting is compromised in Sirt1+/- mice. Repression of PPAR-gamma by Sirt1 is also evident in 3T3-L1 adipocytes, where overexpression of Sirt1 attenuates adipogenesis, and RNA interference of Sirt1 enhances it. In differentiated fat cells, upregulation of Sirt1 triggers lipolysis and loss of fat. As a reduction in fat is sufficient to extend murine lifespan, our results provide a possible molecular pathway connecting calorie restriction to life extension in mammals.

Pubmed ID: 15175761

Authors

  • Picard F
  • Kurtev M
  • Chung N
  • Topark-Ngarm A
  • Senawong T
  • Machado De Oliveira R
  • Leid M
  • McBurney MW
  • Guarente L

Journal

Nature

Publication Data

June 17, 2004

Associated Grants

  • Agency: NIGMS NIH HHS, Id: R01 GM060852
  • Agency: NIGMS NIH HHS, Id: R01 GM060852-02

Mesh Terms

  • 3T3-L1 Cells
  • Adipocytes
  • Animals
  • Biological Transport
  • Caloric Restriction
  • Cell Line
  • DNA-Binding Proteins
  • Gene Deletion
  • Gene Expression
  • Humans
  • Lipid Metabolism
  • Lipolysis
  • Longevity
  • Mice
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 1
  • Nuclear Receptor Co-Repressor 2
  • RNA Interference
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • Sirtuin 1
  • Sirtuins
  • Stilbenes
  • Transcription Factors
  • Triglycerides