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The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis

Nature volume 460, pages 534–537 (2009)Cite this article

Abstract

In fasted mammals, circulating pancreatic glucagon stimulates hepatic gluconeogenesis in part through the CREB regulated transcription coactivator 2 (CRTC2, also referred to as TORC2)1,2. Hepatic glucose production is increased in obesity, reflecting chronic increases in endoplasmic reticulum (ER) stress that promote insulin resistance3. Whether ER stress also modulates the gluconeogenic program directly, however, is unclear. Here we show that CRTC2 functions as a dual sensor for ER stress and fasting signals. Acute increases in ER stress triggered the dephosphorylation and nuclear entry of CRTC2, which in turn promoted the expression of ER quality control genes through an association with activating transcription factor 6 alpha (ATF6α, also known as ATF6)—an integral branch of the unfolded protein response4,5,6,7,8,9. In addition to mediating CRTC2 recruitment to ER stress inducible promoters, ATF6α also reduced hepatic glucose output by disrupting the CREB–CRTC2 interaction and thereby inhibiting CRTC2 occupancy over gluconeogenic genes. Conversely, hepatic glucose output was upregulated when hepatic ATF6α protein amounts were reduced, either by RNA interference (RNAi)-mediated knockdown or as a result of persistent stress in obesity. Because ATF6α overexpression in the livers of obese mice reversed CRTC2 effects on the gluconeogenic program and lowered hepatic glucose output, our results demonstrate how cross-talk between ER stress and fasting pathways at the level of a transcriptional coactivator contributes to glucose homeostasis.

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Figure 1: Nuclear translocation and association of CRTC2 with ATF6α in response to ER stress.
Figure 2: CRTC2 stimulates the expression of ER quality control genes through an association with ATF6α.
Figure 3: CRTC2 mediates cross-talk between hepatic ER stress and fasting pathways.
Figure 4: Reciprocal downregulation of ATF6α and upregulation of CREB in obesity.

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Acknowledgements

This work was supported by grants from the National Institutes of Health, by the Clayton Foundation for Medical Research, by the Keickhefer Foundation, and by the Vincent J. Coates Foundation. We thank N. Miller, S. Hedrick, and Y. Liu for technical assistance and helpful discussions.

Author Contributions Y.W. and L.V. performed in vivo imaging studies; Y.W. performed in vitro and biochemical studies; W.H.F. carried out mass spectrometry analysis. Y.W. and M.M. designed the study, analysed the data, and wrote the paper. All authors reviewed and commented on the manuscript.

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  1. Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA ,

    Yiguo Wang, Liliana Vera, Wolfgang H. Fischer & Marc Montminy

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  1. Yiguo Wang
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  2. Liliana Vera
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Correspondence to Marc Montminy.

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Wang, Y., Vera, L., Fischer, W. et al. The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Nature 460, 534–537 (2009). https://doi.org/10.1038/nature08111

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