Sirt1 Promotes Fat Mobilization in White Adipocytes by Repressing PPAR-gamma

Nature. 2004 Jun 17;429(6993):771-6. doi: 10.1038/nature02583. Epub 2004 Jun 2.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • DNA-Binding Proteins
  • NCOR1 protein, human
  • NCOR2 protein, human
  • Ncor1 protein, mouse
  • Ncor2 protein, mouse
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 1
  • Nuclear Receptor Co-Repressor 2
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • Stilbenes
  • Transcription Factors
  • Triglycerides
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Sirtuins
  • Resveratrol