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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References
Dentin, R. et al. Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449, 366–369 (2007)
Koo, S. H. et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109–1111 (2005)
Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457–461 (2004)
Haze, K., Yoshida, H., Yanagi, H., Yura, T. & Mori, K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell 10, 3787–3799 (1999)
Adachi, Y. et al. ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct. Funct. 33, 75–89 (2008)
Wu, J. et al. ATF6α optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev. Cell 13, 351–364 (2007)
Yoshida, H., Matsui, T., Yamamoto, A., Okada, T. & Mori, K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881–891 (2001)
Lin, J. H. et al. IRE1 signaling affects cell fate during the unfolded protein response. Science 318, 944–949 (2007)
Yamamoto, K. et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6α and XBP1. Dev. Cell 13, 365–376 (2007)
Kahn, B. B. & Flier, J. S. Obesity and insulin resistance. J. Clin. Invest. 106, 473–481 (2000)
Saltiel, A. R. New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell 104, 517–529 (2001)
Screaton, R. A. et al. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 119, 61–74 (2004)
Bittinger, M. A. et al. Activation of cAMP response element-mediated gene expression by regulated nuclear transport of TORC proteins. Curr. Biol. 14, 2156–2161 (2004)
Yoshida, H. et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol. Cell. Biol. 20, 6755–6767 (2000)
Iourgenko, V. et al. Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells. Proc. Natl Acad. Sci. USA 100, 12147–12152 (2003)
Conkright, M. D. et al. TORCs: transducers of regulated CREB activity. Mol. Cell 12, 413–423 (2003)
Oyadomari, S., Harding, H. P., Zhang, Y., Oyadomari, M. & Ron, D. Dephosphorylation of translation initiation factor 2α enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab. 7, 520–532 (2008)
Robinson, L. J., Pang, S., Harris, D. S., Heuser, J. & James, D. E. Translocation of the glucose transporter (GLUT4) to the cell surface in permeabilized 3T3-L1 adipocytes: effects of ATP insulin, and GTP gamma S and localization of GLUT4 to clathrin lattices. J. Cell Biol. 117, 1181–1196 (1992)
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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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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DOI: https://doi.org/10.1038/nature08111
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