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A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange

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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Figure 1: Sequential activation of CRTC2 and FOXO1 during fasting.
Figure 2: CBP and p300 promote CRTC2 acetylation during fasting.
Figure 3: p300 and CBP modulate hepatic CRTC2 activity.
Figure 4: SIRT1 attenuates CRTC2 activity during fasting.

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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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Correspondence to Marc Montminy.

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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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