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

Ji Hyun Lee, Xianlan Wen, Hana Cho, Seung Hoi Koo

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1566-1578
Number of pages13
JournalFASEB Journal
Volume32
Issue number3
DOIs
Publication statusPublished - 2018 Mar

Bibliographical note

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.

Publisher Copyright:
© FASEB.

Keywords

  • CAMP signaling
  • Glucose metabolism
  • Intestinal L cells
  • Transcriptional activator

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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