Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass

Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass

Background: The mechanism by which Roux-en-Y Gastric Bypass (RYGB) increases the secretion of glucagon-like peptide-1 (GLP-1) remains incompletely defined. Here we investigated whether TGR5-mTORC1 signaling mediates the RYGB-induced alteration in GLP-1 production in mice and human beings. Methods: C...

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Main Authors: Hening Zhai, Zhi Li, Miao Peng, Zhaoqi Huang, Tingfeng Qin, Linxi Chen, Hanbing Li, Heng Zhang, Weizhen Zhang, Geyang Xu
Format: Article
Language:English
Published: Elsevier 2018-06-01
Series:EBioMedicine
Online Access:http://www.sciencedirect.com/science/article/pii/S2352396418301907
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spelling doaj-db7d57162c9f40778c901630c19d9eba2020-11-25T01:12:13ZengElsevierEBioMedicine2352-39642018-06-0132201214Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric BypassHening Zhai0Zhi Li1Miao Peng2Zhaoqi Huang3Tingfeng Qin4Linxi Chen5Hanbing Li6Heng Zhang7Weizhen Zhang8Geyang Xu9Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, China; Endoscopy Center, The First Affiliated Hospital of Jinan University, 613 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510630, ChinaDepartment of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, ChinaDepartment of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, ChinaDepartment of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, ChinaDepartment of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, ChinaDepartment of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, ChinaDepartment of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, ChinaDepartment of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, ChinaShenzhen University Diabetes Center, Shenzhen University Health Science Center, Shenzhen, Guangdong 518060, China; Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109-0346, USADepartment of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, China; Corresponding author at Jinan University, No. 601, West Huangpu Avenue, Tianhe District, Guangzhou, Guangdong, 510632, China. Tel.: 0086 20 85220260; Fax: 0086 20 85221343Background: The mechanism by which Roux-en-Y Gastric Bypass (RYGB) increases the secretion of glucagon-like peptide-1 (GLP-1) remains incompletely defined. Here we investigated whether TGR5-mTORC1 signaling mediates the RYGB-induced alteration in GLP-1 production in mice and human beings. Methods: Circulating bile acids, TGR5-mTORC1 signaling, GLP-1 synthesis and secretion were determined in lean or obese male C57BL/6 mice with or without RYGB operation, as well as in normal glycemic subjects, obese patients with type 2 diabetes before and after RYGB. Results: Positive relationships were observed among circulating bile acids, ileal mechanistic target of rapamycin complex 1 (mTORC1) signaling and GLP-1 during changes in energy status in the present study. RYGB increased circulating bile acids, ileal Takeda G protein-coupled receptor 5 (TGR5) and mTORC1 signaling activity, as well as GLP-1 production in both mice and human subjects. Inhibition of ileal mTORC1 signaling by rapamycin significantly attenuated the stimulation of bile acid secretion, TGR5 expression and GLP-1 synthesis induced by RYGB in lean and diet-induced obese mice. GLP-1 production and ileal TGR5-mTORC1 signaling were positively correlated with plasma deoxycholic acid (DCA) in mice. Treatment of STC-1 cells with DCA stimulated the production of GLP-1. This effect was associated with a significant enhancement of TGR5-mTORC1 signaling. siRNA knockdown of mTORC1 or TGR5 abolished the enhancement of GLP-1 synthesis induced by DCA. DCA increased interaction between mTOR-regulatory-associated protein of mechanistic target of rapamycin (Raptor) and TGR5 in STC-1 cells. Interpretation: Deoxycholic acid-TGR5-mTORC1 signaling contributes to the up-regulation of GLP-1 production after RYGB. Keywords: Deoxycholic acid, GLP-1, mTORC1, RYGB, TGR5http://www.sciencedirect.com/science/article/pii/S2352396418301907
collection DOAJ
language English
format Article
sources DOAJ
author Hening Zhai
Zhi Li
Miao Peng
Zhaoqi Huang
Tingfeng Qin
Linxi Chen
Hanbing Li
Heng Zhang
Weizhen Zhang
Geyang Xu
spellingShingle Hening Zhai
Zhi Li
Miao Peng
Zhaoqi Huang
Tingfeng Qin
Linxi Chen
Hanbing Li
Heng Zhang
Weizhen Zhang
Geyang Xu
Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass
EBioMedicine
author_facet Hening Zhai
Zhi Li
Miao Peng
Zhaoqi Huang
Tingfeng Qin
Linxi Chen
Hanbing Li
Heng Zhang
Weizhen Zhang
Geyang Xu
author_sort Hening Zhai
title Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass
title_short Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass
title_full Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass
title_fullStr Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass
title_full_unstemmed Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin Complex 1 Signaling Contributes to the Increment of Glucagon-Like Peptide-1 Production after Roux-en-Y Gastric Bypass
title_sort takeda g protein-coupled receptor 5-mechanistic target of rapamycin complex 1 signaling contributes to the increment of glucagon-like peptide-1 production after roux-en-y gastric bypass
publisher Elsevier
series EBioMedicine
issn 2352-3964
publishDate 2018-06-01
description Background: The mechanism by which Roux-en-Y Gastric Bypass (RYGB) increases the secretion of glucagon-like peptide-1 (GLP-1) remains incompletely defined. Here we investigated whether TGR5-mTORC1 signaling mediates the RYGB-induced alteration in GLP-1 production in mice and human beings. Methods: Circulating bile acids, TGR5-mTORC1 signaling, GLP-1 synthesis and secretion were determined in lean or obese male C57BL/6 mice with or without RYGB operation, as well as in normal glycemic subjects, obese patients with type 2 diabetes before and after RYGB. Results: Positive relationships were observed among circulating bile acids, ileal mechanistic target of rapamycin complex 1 (mTORC1) signaling and GLP-1 during changes in energy status in the present study. RYGB increased circulating bile acids, ileal Takeda G protein-coupled receptor 5 (TGR5) and mTORC1 signaling activity, as well as GLP-1 production in both mice and human subjects. Inhibition of ileal mTORC1 signaling by rapamycin significantly attenuated the stimulation of bile acid secretion, TGR5 expression and GLP-1 synthesis induced by RYGB in lean and diet-induced obese mice. GLP-1 production and ileal TGR5-mTORC1 signaling were positively correlated with plasma deoxycholic acid (DCA) in mice. Treatment of STC-1 cells with DCA stimulated the production of GLP-1. This effect was associated with a significant enhancement of TGR5-mTORC1 signaling. siRNA knockdown of mTORC1 or TGR5 abolished the enhancement of GLP-1 synthesis induced by DCA. DCA increased interaction between mTOR-regulatory-associated protein of mechanistic target of rapamycin (Raptor) and TGR5 in STC-1 cells. Interpretation: Deoxycholic acid-TGR5-mTORC1 signaling contributes to the up-regulation of GLP-1 production after RYGB. Keywords: Deoxycholic acid, GLP-1, mTORC1, RYGB, TGR5
url http://www.sciencedirect.com/science/article/pii/S2352396418301907
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