A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange (original) (raw)

Nature volume 456, pages 269–273 (2008)Cite this article

Abstract

During early fasting, increases in skeletal muscle proteolysis liberate free amino acids for hepatic gluconeogenesis in response to pancreatic glucagon. Hepatic glucose output diminishes during the late protein-sparing phase of fasting, when ketone body production by the liver supplies compensatory fuel for glucose-dependent tissues1,2,3,4. Glucagon stimulates the gluconeogenic program by triggering the dephosphorylation and nuclear translocation of the CREB regulated transcription coactivator 2 (CRTC2; also known as TORC2), while parallel decreases in insulin signalling augment gluconeogenic gene expression through the dephosphorylation and nuclear shuttling of forkhead box O1 (FOXO1)5,6,7. Here we show that a fasting-inducible switch, consisting of the histone acetyltransferase p300 and the nutrient-sensing deacetylase sirtuin 1 (SIRT1), maintains energy balance in mice through the sequential induction of CRTC2 and FOXO1. After glucagon induction, CRTC2 stimulated gluconeogenic gene expression by an association with p300, which we show here is also activated by dephosphorylation at Ser 89 during fasting. In turn, p300 increased hepatic CRTC2 activity by acetylating it at Lys 628, a site that also targets CRTC2 for degradation after its ubiquitination by the E3 ligase constitutive photomorphogenic protein (COP1)8. Glucagon effects were attenuated during late fasting, when CRTC2 was downregulated owing to SIRT1-mediated deacetylation and when FOXO1 supported expression of the gluconeogenic program. Disrupting SIRT1 activity, by liver-specific knockout of the Sirt1 gene or by administration of a SIRT1 antagonist, increased CRTC2 activity and glucose output, whereas exposure to SIRT1 agonists reduced them. In view of the reciprocal activation of FOXO1 and its coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α, encoded by Ppargc1a) by SIRT1 activators9,10,11,12, our results illustrate how the exchange of two gluconeogenic regulators during fasting maintains energy balance.

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Acknowledgements

We thank M. Kahn for the gift of phospho-specific p300 antiserum and L. Vera for technical assistance. We also thank R. Shaw and M. Mihaylova for sharing results on p300 phosphorylation. This work was supported by grants from the National Institutes of Health, the Clayton Medical Research Foundation, Inc., the Hillblom Foundation (to Y.L.), and the Kieckhefer Foundation.

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Author notes

  1. Yi Liu, Renaud Dentin and Danica Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd, La Jolla, California 92037, USA ,
    Yi Liu, Renaud Dentin, Susan Hedrick, Kim Ravnskjaer & Marc Montminy
  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,
    Danica Chen & Leonard Guarente
  3. Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA,
    Simon Schenk & Jerrold Olefsky
  4. Sirtris Pharmaceuticals Inc., 200 Technology Square, Cambridge, Massachusetts 02139, USA ,
    Jill Milne
  5. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 North Wolfe Street, 316 Hunterian Building, Baltimore, Maryland 21205, USA,
    David J. Meyers & Phil Cole
  6. The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA ,
    John Yates III

Authors

  1. Yi Liu
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  2. Renaud Dentin
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  3. Danica Chen
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  4. Susan Hedrick
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  5. Kim Ravnskjaer
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  6. Simon Schenk
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  7. Jill Milne
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  8. David J. Meyers
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  9. Phil Cole
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  10. John Yates III
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  11. Jerrold Olefsky
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  12. Leonard Guarente
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  13. Marc Montminy
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Corresponding author

Correspondence toMarc Montminy.

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Competing interests

L.G. is a member of the Advisory Board at Sirtris. J.M. was an employee at Sirtris.

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Liu, Y., Dentin, R., Chen, D. et al. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange.Nature 456, 269–273 (2008). https://doi.org/10.1038/nature07349

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Editorial Summary

Maintaining energy balance in fasting

A fasting-inducible switch, consisting of the histone acetyl transferase p300 and the nutrient-sensing NAD+-dependent deacetylase SIRT1, is shown to maintain energy balance during fasting by promoting the sequential induction of the transcription factors TORC2 and FOXO1. This illustrates how the exchange of two gluconeogenic regulators during fasting maintains energy balance.