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

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.

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Acknowledgements

We thank P. Vazquez for important discussions on the project. We also acknowledge members of the Puigserver laboratory for helpful comments on this work, especially T. Cunningham and S.-H. Kim for technical assistance. Some constructs or reagents were obtained from W. Gu, L. Guarente, D. Robinson and M. Stoffel. We also thank M. Montminy for the PGC-1α polyclonal antibody. The protocols for NAD+ and NADH measurements were obtained from S.-J. Lin. Part of these studies was supported by awards from the Ellison Medical Foundation and the American Federation for Aging Research (P.P.).

Author information

Correspondence to Pere Puigserver.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1

SIRT1 protein is not regulated by forskolin/dexamethasone or insulin. (PDF 43 kb)

Supplementary Figure 2

SIRT1 regulation at the protein level. A. Pulse-chase experiment showing that incubation in pyruvate does not change SIRT1 half-life. B. Pulse labelling experiment showing an increase in labelled SIRT1 when pyruvate is added to pulse media. (PDF 195 kb)

Supplementary Figure 3

In-vivo and In-vitro interaction of SIRT1 and PGC-1α. A. In-vivo interaction of overexpressed SIRT1 and PGC-1α in 293T cells. B. In-vitro interaction of 35S labelled SIRT1 and GST-PGC-1α. (PDF 119 kb)

Supplementary Figure 4

Mapping of PGC-1α acetylation sites. A. Identified acetylated PGC-1α peptides. B. Identification of acetylation at PGC-1α residue K183. (PDF 112 kb)

Supplementary Figure 5

SIRT1 is in a complex that includes PGC-1α and HNF4α. A. In 293T cells endogenous SIRT1 co-immunoprecipitates with HNF4α only when PGC-1α is overexpressed. B. Immunoprecipitation of endogenous SIRT1 pulls down endogenous PGC-1α and HNF4α in FAO cells. (PDF 106 kb)

Supplementary Figure 6

SIRT1 siRNA decreases SIRT1 levels but does not affect PGC-1α protein. (PDF 49 kb)

Supplementary Figure 7

Chromatin immunoprecipitation of SIRT1 and PGC-1α showing both are present on gluconeogenic promoters. (PDF 60 kb)

Supplementary Figure 8

Table of RT-PCR primers. (PDF 12 kb)

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Further reading

Figure 1: Nutritional regulation of SIRT1 protein and NAD+ levels in liver and hepatocytes.
Figure 2: SIRT1 interacts with and deacetylates PGC-1α.
Figure 3: Nutrient regulation of gluconeogenic and glycolytic genes is controlled through SIRT1.
Figure 4: Nutrient regulation of PGC-1α function on glucose output depends on SIRT1.

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