Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.
Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1--which modulates ageing in several species--controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1alpha. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1alpha at specific lysine residues in an NAD(+)-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1alpha, but does not regulate the effects of PGC-1alpha on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1alpha. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.
Rodgers
Joseph T
JT
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Lerin
Carlos
C
Haas
Wilhelm
W
Gygi
Steven P
SP
Spiegelman
Bruce M
BM
Puigserver
Pere
P
D000107:Acetylation; D000818:Animals; D031204:Caloric Restriction; D000242:Cyclic AMP / Q000494:pharmacology; D005215:Fasting / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008136:Longevity; D008239:Lysine / Q000378:metabolism; D051379:Mice; D009243:NAD / Q000378:metabolism; D009752:Nutritional Status; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011485:Protein Binding; D019289:Pyruvic Acid / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors
D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D009243:NAD; D019344:Lactic Acid; D019289:Pyruvic Acid; D000242:Cyclic AMP; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D005947:Glucose; D008239:Lysine