Stress and Sugar Rushes

Science Signaling  04 Aug 2009:
Vol. 2, Issue 82, pp. ec257
DOI: 10.1126/scisignal.282ec257

CRTC2 [CREB (cAMP response element–binding protein)–regulated transcription coactivator 2; also known as TORC2] binds to the transcription factor CREB to modulate hepatic gluconeogenesis. Wang et al. found that treatment of primary hepatocytes with thapsigargin or tunicamycin to induce ER stress promoted activation of CRTC2, as assessed by dephosphorylation and nuclear translocation. However, these treatments inhibited a luciferase reporter (CRE-luc) that detects CREB-CRTC2 activity. A proteomic screen identified ATF6α (activating transcription factor 6α), a transcription factor that translocates from the ER to the nucleus during ER stress, as a binding partner for CRTC2. In thapsigargin- or tunicamycin-treated hepatocytes, CRTC2 and ATF6α were detected on the promoter of Xbp1 (X-box binding protein 1), a gene that encodes a transcription factor induced by ER stress. Furthermore, tunicamycin injection into mice increased hepatic activity of a luciferase reporter for XBP1 (XBP1-luc) and transcription of ER stress–induced genes, including Xbp1; these effects were enhanced by CRTC2 overexpression and reduced by RNA interference directed against CRTC2. Because the binding sites for ATF6α and CREB on CRTC2 overlapped, the authors investigated whether ATF6α competes with CREB for CRTC2. Overexpression in hepatocytes of an ATF6α mutant that was constitutively localized to the nucleus (ATF6-N) reduced association of CRTC2 with CREB, recruitment of CRTC2 to the glucose-6-phosphatase promoter (a CREB target gene), and gluconeogenesis (as measured by glucose production). During extended periods of ER stress, which occur in obesity, ATF6α is degraded, an event that would be expected to impair ER stress responses while enhancing gluconeogenesis. Accordingly, obese mice, whether because of genetic engineering (db/db) or high-fat diets, showed reduced XBP1-luc reporter activity in combination with increased CRE-luc activity and blood glucose concentrations compared with lean mice; these differences were decreased by ATF6-N overexpression in either mouse model of obesity. Thus, CRTC2 appears to act as a switch between ER stress responses and gluconeogenesis, and the balance between these two states is disrupted in obesity.

Y. Wang, L. Vera, W. H. Fischer, M. Montminy, The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Nature 460, 534–537 (2009).[PubMed]