Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1

• Published in: Nature Vol. 434; no. 7029; pp. 113 - 118
• Main Authors: Rodgers, J.T, Lerin, C, Haas, W, Gygi, S.P, Spiegelman, B.M, Puigserver, P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 03.03.2005; Nature Publishing Group
• Subjects: Biological and medical sciences; carbohydrate metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; esterases; gene expression regulation; gluconeogenesis; glucose; glycolysis; hepatocytes; histone deacetylase; liver; Medical sciences; mice; pyruvic acid; starvation; transcription factors; Endocrinopathy; Senescence; Fasting; Digestive system; Diabetes mellitus; Liver; Homeostasis; Glucose; Metabolism; Protein; Vertebrata; Mitochondria; Mammalia; Lysine; Nutrient
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature03354

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-1α. 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-1α at specific lysine residues in an NAD+-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1α, but does not regulate the effects of PGC-1α on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1α 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-1α. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.