CREB/CRTC2 controls GLP‐1‐dependent regulation of glucose homeostasis. Issue 3 (3rd January 2018) - Lee, Ji‐Hyun
Abstract : Glucagon‐like peptide 1 (GLP‐1) is a major incretin that controls glucose homeostasis. The secretion of mature GLP‐1 is regulated via GPCRs, including bile acid receptor G protein‐coupled bile acid receptor 1, which uses cAMP signaling to enhance the exocytosis of GLP‐1‐containing vesicles. However, the role of cAMP‐mediated transcription has not been clearly demonstrated to date. In this study, we explored the role of cAMP response element‐binding protein/CREB‐regulated transcription coactivator 2 (CREB/CRTC2)‐dependent transcription on GLP‐1 secretion in the L cells. We found that the reduced CREB/CRTC2 activity impaired the cAMP‐dependent increase in GLP‐1 secretion, whereas expression of constitutively active CRTC2 increased GLP‐1 exocytosis from the L cells. Close investigation revealed that expression of not only proglucagon but also PC1/3, an endopeptidase for GLP‐1 maturation, is transcriptionally regulated by CREB/CRTC2. Furthermore, expression of peroxisome proliferator‐activating receptor coactivator 1 α is also reduced upon depletion of CRTC2, leading to the decreased expression of oxidative phosphorylation (OxPhos) genes, reduced ATP levels, and calcium concentrations in the L cells. Finally, we observed that intestine‐specific CRTC2 knockout mice displayed reduced GLP‐1 expression, leading to the lower plasma GLP‐1 levels, impaired glucose tolerance, and decreased insulin‐containing β cells in pancreatic islets. Our data show that the CREB/CRTC2‐dependent transcriptional pathway is critical for regulating glucose homeostasis by controlling production of GLP‐1 from the L cells at the level of transcription, maturation, and exocytosis.—Lee, J.‐H., Wen, X., Cho, H., Koo, S.‐H. CREB/CRTC2 controls GLP‐1‐dependent regulation of glucose homeostasis. FASEB J. 32, 1566‐1578 (2018). www.fasebj.org