1. Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
2. Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
3. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

Correspondence to: Pere Puigserver¹ Correspondence and requests for materials should be addressed to P.P. (Email: ppuigse1@bs.jhmi.edu).

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^{1, 2, 3} —controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1. 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-1 at specific lysine residues in an NAD⁺-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1, but does not regulate the effects of PGC-1 on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1 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-1. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.

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