1. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
2. Laboratory of Molecular Pharmacology, Department of Pharmaceutical Sciences, College of Pharmacy and Environmental Health Science Center, Oregon State University, Corvallis, Oregon 97331-3507, USA
3. Graduate Program in Basic and Applied Biology, ICBAS, University of Porto, 4099-003, Portugal
4. Ottawa Regional Cancer Centre and Department of Medicine, University of Ottawa, Ontario K1H 1C4, Canada

Correspondence to: Leonard Guarente¹ Email: leng@mit.edu

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- (peroxisome proliferator-activated receptor-), including genes mediating fat storage. Sirt1 represses PPAR- 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- 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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