Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ

Frédéric Picard, Martin Kurtev, Namjin Chung, Acharawan Topark-Ngarm, Thanaset Senawong, Rita Machado de Oliveira, Mark Leid, Michael W. McBurney and Leonard Guarente ()
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Frédéric Picard: Massachusetts Institute of Technology
Martin Kurtev: Massachusetts Institute of Technology
Namjin Chung: Massachusetts Institute of Technology
Acharawan Topark-Ngarm: College of Pharmacy and Environmental Health Science Center, Oregon State University
Thanaset Senawong: College of Pharmacy and Environmental Health Science Center, Oregon State University
Rita Machado de Oliveira: Massachusetts Institute of Technology
Mark Leid: College of Pharmacy and Environmental Health Science Center, Oregon State University
Michael W. McBurney: University of Ottawa
Leonard Guarente: Massachusetts Institute of Technology

Nature, 2004, vol. 429, issue 6993, 771-776

Abstract: Abstract Calorie restriction extends lifespan in organisms ranging from yeast to mammals1. In yeast, the SIR2 gene mediates the life-extending effects of calorie restriction2. 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-γ (peroxisome proliferator-activated receptor-γ), including genes mediating fat storage. Sirt1 represses PPAR-γ 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-γ 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 lifespan3, our results provide a possible molecular pathway connecting calorie restriction to life extension in mammals.

Date: 2004
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DOI: 10.1038/nature02583

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