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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.

Pubmed ID: 15744310


  • Rodgers JT
  • Lerin C
  • Haas W
  • Gygi SP
  • Spiegelman BM
  • Puigserver P



Publication Data

March 3, 2005

Associated Grants


Mesh Terms

  • Acetylation
  • Animals
  • Caloric Restriction
  • Cyclic AMP
  • Fasting
  • Gene Expression Regulation
  • Gluconeogenesis
  • Glucose
  • Glycolysis
  • Hepatocytes
  • Homeostasis
  • Insulin
  • Lactic Acid
  • Liver
  • Longevity
  • Lysine
  • Mice
  • NAD
  • Nutritional Status
  • Protein Binding
  • Pyruvic Acid
  • RNA, Messenger
  • Rats
  • Sirtuin 1
  • Sirtuins
  • Trans-Activators
  • Transcription Factors