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

Joseph T. Rodgers, Carlos Lerin, Wilhelm Haas, Steven P. Gygi, Bruce M. Spiegelman and Pere Puigserver ()
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Joseph T. Rodgers: Johns Hopkins University School of Medicine
Carlos Lerin: Johns Hopkins University School of Medicine
Wilhelm Haas: Harvard Medical School
Steven P. Gygi: Harvard Medical School
Bruce M. Spiegelman: Harvard Medical School
Pere Puigserver: Johns Hopkins University School of Medicine

Nature, 2005, vol. 434, issue 7029, 113-118

Abstract: 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 species1,2,3 —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.

Date: 2005
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DOI: 10.1038/nature03354

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