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.
Pubmed ID: 15175761 RIS Download
3T3-L1 Cells | Adipocytes | Animals | Biological Transport | Caloric Restriction | Cell Line | DNA-Binding Proteins | Gene Deletion | Gene Expression | Humans | Lipid Metabolism | Lipolysis | Longevity | Mice | Nuclear Proteins | Nuclear Receptor Co-Repressor 1 | Nuclear Receptor Co-Repressor 2 | RNA Interference | Receptors, Cytoplasmic and Nuclear | Repressor Proteins | Sirtuin 1 | Sirtuins | Stilbenes | Transcription Factors | Triglycerides