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, Pere Puigserver

    Research output: Contribution to journalArticle

    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-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.

    Original languageEnglish (US)
    Pages (from-to)113-118
    Number of pages6
    JournalNature
    Volume434
    Issue number7029
    DOIs
    StatePublished - Mar 3 2005

    Fingerprint

    Fasting
    Homeostasis
    Pyruvic Acid
    Glucose
    Food
    Liver
    Caloric Restriction
    Mitochondrial Genes
    NAD
    Genes
    Lysine
    Blood Glucose
    Mammals
    Hormones
    Proteins

    ASJC Scopus subject areas

    • General

    Cite this

    Rodgers, J. T., Lerin, C., Haas, W., Gygi, S. P., Spiegelman, B. M., & Puigserver, P. (2005). Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature, 434(7029), 113-118. https://doi.org/10.1038/nature03354

    Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. / Rodgers, Joseph T.; Lerin, Carlos; Haas, Wilhelm; Gygi, Steven P.; Spiegelman, Bruce M.; Puigserver, Pere.

    In: Nature, Vol. 434, No. 7029, 03.03.2005, p. 113-118.

    Research output: Contribution to journalArticle

    Rodgers, JT, Lerin, C, Haas, W, Gygi, SP, Spiegelman, BM & Puigserver, P 2005, 'Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1', Nature, vol. 434, no. 7029, pp. 113-118. https://doi.org/10.1038/nature03354
    Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature. 2005 Mar 3;434(7029):113-118. https://doi.org/10.1038/nature03354
    Rodgers, Joseph T. ; Lerin, Carlos ; Haas, Wilhelm ; Gygi, Steven P. ; Spiegelman, Bruce M. ; Puigserver, Pere. / Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. In: Nature. 2005 ; Vol. 434, No. 7029. pp. 113-118.
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