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

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

doi:10.1096/fj.201700845R

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

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

Research output: Contribution to journal › Article › peer-review

32 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 language	English
Pages (from-to)	1566-1578
Number of pages	13
Journal	FASEB Journal
Volume	32
Issue number	3
DOIs	https://doi.org/10.1096/fj.201700845R
Publication status	Published - 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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title = "CREB/CRTC2 controls GLP-1-dependent regulation of glucose homeostasis",

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.",

keywords = "CAMP signaling, Glucose metabolism, Intestinal L cells, Transcriptional activator",

author = "Lee, {Ji Hyun} and Xianlan Wen and Hana Cho and Koo, {Seung Hoi}",

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: {\textcopyright} FASEB.",

year = "2018",

month = mar,

doi = "10.1096/fj.201700845R",

language = "English",

volume = "32",

pages = "1566--1578",

journal = "FASEB Journal",

issn = "0892-6638",

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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. Publisher Copyright: © FASEB.

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.

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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