The DOI matches its Crossref record; 18 of the 18 references it cites were found in a registry or an index.
The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis
Open accessAbstract
In fasted mammals, circulating pancreatic glucagon stimulates hepatic gluconeogenesis in part through the CREB regulated transcription coactivator 2 (CRTC2, also referred to as TORC2). Hepatic glucose production is increased in obesity, reflecting chronic increases in endoplasmic reticulum (ER) stress that promote insulin resistance. 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 response. 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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Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
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Obesity and insulin resistance
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The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism
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ATF6α Optimizes Long-Term Endoplasmic Reticulum Function to Protect Cells from Chronic Stress
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Cited by
Endoplasmic reticulum stress and the inflammatory basis of metabolic disease
Hotamisligil, G. S. (2010) · Cell · doi:10.1016/j.cell.2010.02.034 · Cited by 2,802
ER stress-induced cell death mechanisms
Sano, R., & Reed, J. C. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.06.028 · Cited by 1,988
Protein misfolding in the endoplasmic reticulum as a conduit to human disease
Wang, M., & Kaufman, R. J. (2016) · Nature · doi:10.1038/nature17041 · Cited by 1,630
CREB and the CRTC co-activators: sensors for hormonal and metabolic signals
Altarejos, J. Y., & Montminy, M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3072 · Cited by 1,040
Self-citationThe impact of the unfolded protein response on human disease
Wang, S., & Kaufman, R. J. (2012) · Journal of Cell Biology · doi:10.1083/jcb.201110131 · Cited by 984
Metadata
- Authors
- Wang, Y., Vera, L., Fischer, W. H., & Montminy, M.
- Venue
- Nature
- Published
- 2009-06-21
- Volume
- 460
- Issue
- 7254
- Pages
- 534-537
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1990607211
- Cited by
- 297
- References
- 18
- FWCI
- 9.35
- Type
- journal article
- Language
- en
- Open access
- green
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