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PMID:15175761
| Citation |
Picard, F, Kurtev, M, Chung, N, Topark-Ngarm, A, Senawong, T, Machado De Oliveira, R, Leid, M, McBurney, MW and Guarente, L (2004) Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429:771-6 |
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| Abstract |
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. |
| Links |
PubMed PMC2820247 Online version:10.1038/nature02583 |
| Keywords |
3T3-L1 Cells; Adipocytes/metabolism; Animals; Biological Transport; Caloric Restriction; Cell Line; DNA-Binding Proteins/metabolism; Gene Deletion; Gene Expression; Humans; Lipid Metabolism; Lipolysis; Longevity/physiology; Mice; Nuclear Proteins/metabolism; Nuclear Receptor Co-Repressor 1; Nuclear Receptor Co-Repressor 2; RNA Interference; Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear/metabolism; Repressor Proteins/metabolism; Sirtuin 1; Sirtuins/deficiency; Sirtuins/genetics; Sirtuins/metabolism; Stilbenes/pharmacology; Transcription Factors/antagonists & inhibitors; Transcription Factors/metabolism; Triglycerides/metabolism |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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