Nutrient Control of Glucose Homeostasis Through a Complex of PGC-1alpha and SIRT1

Nature. 2005 Mar 3;434(7029):113-8. doi: 10.1038/nature03354.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Caloric Restriction
  • Cyclic AMP / pharmacology
  • Fasting / metabolism
  • Gene Expression Regulation / drug effects
  • Gluconeogenesis / drug effects
  • Gluconeogenesis / genetics
  • Glucose / metabolism*
  • Glycolysis / drug effects
  • Glycolysis / genetics
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Homeostasis*
  • Insulin / pharmacology
  • Lactic Acid / metabolism
  • Liver / cytology
  • Liver / drug effects
  • Liver / metabolism
  • Longevity
  • Lysine / metabolism
  • Mice
  • NAD / metabolism
  • Nutritional Status
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Protein Binding
  • Pyruvic Acid / metabolism
  • Pyruvic Acid / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Sirtuin 1
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Trans-Activators / metabolism*
  • Transcription Factors

Substances

  • Insulin
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • RNA, Messenger
  • Trans-Activators
  • Transcription Factors
  • NAD
  • Lactic Acid
  • Pyruvic Acid
  • Cyclic AMP
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Sirtuins
  • Glucose
  • Lysine