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CREB/CRTC2 controls GLP-1-dependent regulation of glucose homeostasis

Authors
Lee, Ji-HyunWen, XianlanCho, HanaKoo, Seung-Hoi
Issue Date
3월-2018
Publisher
FEDERATION AMER SOC EXP BIOL
Keywords
cAMP signaling; transcriptional activator; glucose metabolism; intestinal L cells
Citation
FASEB JOURNAL, v.32, no.3, pp.1566 - 1578
Indexed
SCIE
SCOPUS
Journal Title
FASEB JOURNAL
Volume
32
Number
3
Start Page
1566
End Page
1578
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/77280
DOI
10.1096/fj.201700845R
ISSN
0892-6638
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 a 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 beta 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.
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생명과학대학 (생명과학부)
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