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.
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We thank B. Spiegelman for the gift of constructs and for discussion; T. Kouzarides and T. Heinzel for Sirt1 and NCoR constructs, respectively; and R. Frye for the anti-Sirt1 antiserum. The Guarente laboratory was supported by grants from the NIH, the Ellison Medical Foundation, and the Howard and Linda Stern Fund. Studies in the Leid laboratory were supported by grants from the National Institutes of Health and by a NIEHS Center grant to the Oregon State University Environmental Health Sciences Center. T.S. was supported by a graduate fellowship from the Royal Thai Government. R.M.O. is supported by the Portuguese Foundation for Science and Technology. M.K. is a Howard Hughes undergraduate research fellow. F.P. was supported in part by a postdoctoral fellowship from the Canadian Institutes of Health Research.
L. Guarente is a founder, consultant and stockholder of Elixir Pharmaceuticals.
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