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

Article

关键词: CEREVISIAE LIFE-SPAN;    SACCHAROMYCES-CEREVISIAE;    CALORIE RESTRICTION;    TRANSCRIPTION FACTORS;    INSULIN-RESISTANCE;    3T3-L1 ADIPOCYTES;    ADIPOSE-TISSUE;    RECEPTOR;    DIFFERENTIATION;    ADIPOGENESIS;   

DOI  :  10.1038/nature02583

来源: SCIE

【 摘 要 】

Calorie restriction extends lifespan in organisms ranging from yeast to mammals(1). In yeast, the SIR2 gene mediates the life-extending effects of calorie restriction(2). 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(3), our results provide a possible molecular pathway connecting calorie restriction to life extension in mammals.

【 授权许可】

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