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

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

Research output: Contribution to journalArticle

4 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 1

Fingerprint

Cyclic AMP Response Element-Binding Protein
Glucagon-Like Peptide 1
Transcription
Homeostasis
Glucose
Exocytosis
Bile Acids and Salts
Proglucagon
Peroxisome Proliferators
Incretins
Endopeptidases
Critical Pathways
Glucose Intolerance
Oxidative Phosphorylation
G-Protein-Coupled Receptors
Islets of Langerhans
Knockout Mice
Intestines
Genes
Adenosine Triphosphate

Keywords

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

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

CREB/CRTC2 controls GLP-1-dependent regulation of glucose homeostasis. / Lee, Ji Hyun; Wen, Xianlan; Cho, Hana; Koo, Seung-Hoi.

In: FASEB Journal, Vol. 32, No. 3, 01.03.2018, p. 1566-1578.

Research output: Contribution to journalArticle

Lee, Ji Hyun ; Wen, Xianlan ; Cho, Hana ; Koo, Seung-Hoi. / CREB/CRTC2 controls GLP-1-dependent regulation of glucose homeostasis. In: FASEB Journal. 2018 ; Vol. 32, No. 3. pp. 1566-1578.
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