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.
Picard
Frédéric
F
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Kurtev
Martin
M
Chung
Namjin
N
Topark-Ngarm
Acharawan
A
Senawong
Thanaset
T
Machado De Oliveira
Rita
R
Leid
Mark
M
McBurney
Michael W
MW
Guarente
Leonard
L
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D031204:Caloric Restriction; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D050356:Lipid Metabolism; D008066:Lipolysis; D008136:Longevity / Q000502:physiology*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D000077185:Resveratrol; D056564:Sirtuin 1; D037761:Sirtuins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D004268:DNA-Binding Proteins; C539127:NCOR1 protein, human; C539130:NCOR2 protein, human; C539128:Ncor1 protein, mouse; C539131:Ncor2 protein, mouse; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D013267:Stilbenes; D014157:Transcription Factors; D014280:Triglycerides; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol