TY - JOUR
T1 - CREB/CRTC2 controls GLP-1-dependent regulation of glucose homeostasis
AU - Lee, Ji Hyun
AU - Wen, Xianlan
AU - Cho, Hana
AU - Koo, Seung Hoi
N1 - Funding Information:
The authors thank Prof. Daniel Drucker (University of Toronto, Toronto, ON, Canada) and Prof. Toru Hira (Hokkaido University, Sapporo, Hokkaido, Japan) for kindly providing us the GLUTag L cells and Prof. Minsun Kim (Asan Medical Center, Seoul, Korea) for kindly providing us with the villin-Cre transgenic mice. The authors thank members of the Koo Laboratory for critical review of this manuscript. This work was supported by the National Research Foundation of Korea (Grants NRF-2015R1A2A1A01006687, NRF-2012M3A9B6055345, NRF-2015R1A5A1009024, and NRF-2017M3A9D5A01052447), funded by the Ministry of Science and ICT, Korea, and a grant from Korea University. The authors declare no conflicts of interests.
PY - 2018/3
Y1 - 2018/3
N2 - 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 cAMPsignaling to enhance the exocytosis ofGLP-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 glucosehomeostasisby controllingproductionofGLP-1 fromtheLcells at the levelof transcription, maturation, and exocytosis.
AB - 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 cAMPsignaling to enhance the exocytosis ofGLP-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 glucosehomeostasisby controllingproductionofGLP-1 fromtheLcells at the levelof transcription, maturation, and exocytosis.
KW - CAMP signaling
KW - Glucose metabolism
KW - Intestinal L cells
KW - Transcriptional activator
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U2 - 10.1096/fj.201700845R
DO - 10.1096/fj.201700845R
M3 - Article
C2 - 29118086
AN - SCOPUS:85043584813
VL - 32
SP - 1566
EP - 1578
JO - The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
JF - The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
SN - 1530-6860
IS - 3
ER -