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

• Published in: EBioMedicine Vol. 32; pp. 201 - 214
• Main Authors: Zhai, Hening, Li, Zhi, Peng, Miao, Huang, Zhaoqi, Qin, Tingfeng, Chen, Linxi, Li, Hanbing, Zhang, Heng, Zhang, Weizhen, Xu, Geyang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2018; Elsevier
• Subjects: Advanced Basic Science; Animals; Bile Acids and Salts - blood; Blood Glucose; Deoxycholic acid; Deoxycholic Acid - blood; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - pathology; Diabetes Mellitus, Type 2 - surgery; Gastric Bypass - adverse effects; Gene Expression Regulation - genetics; GLP-1; Glucagon-Like Peptide 1 - biosynthesis; Glucagon-Like Peptide 1 - genetics; Humans; Insulin Resistance - genetics; Internal Medicine; Male; Mechanistic Target of Rapamycin Complex 1 - genetics; Mice; Mice, Obese; Middle Aged; mTORC1; Obesity - blood; Obesity - genetics; Obesity - pathology; Obesity - surgery; Receptors, G-Protein-Coupled - genetics; Research Paper; RYGB; Signal Transduction - genetics; TGR5; FXR; DCA; GLP-1; S6; RYGB; ip; Raptor; S6K1; Deoxycholic acid; TGR5; BAs; mTOR; Cyp7a1; mTORC1; Farnesoid X receptor; Roux-en-Y gastric bypass; mechanistic target of rapamycin; Intraperitoneal; Ribosomal protein subunit 6 kinase 1; Takeda G protein-coupled receptor 5; Bile acids; Regulatory-associated protein of mechanistic target of rapamycin; Cytochrome P450 family 7 subfamily A member 1; Ribosomal protein S6; Glucagon-like peptide-1; mechanistic target of rapamycin complex 1
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2018.05.026

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. 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. 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. Deoxycholic acid-TGR5-mTORC1 signaling contributes to the up-regulation of GLP-1 production after RYGB. •Ileal mTORC1 signaling activity and GLP-1 production are up-regulated by RYGB in both rodents and human subjects.•Manipulation of intestinal mTORC1 signaling alters the up-regulation of GLP-1 induced by RYGB.•Ileal TGR5-mTORC1 signaling and GLP-1 production are positively correlative with plasma deoxycholic acid in mice.•Deoxycholic acid enhances synthesis and secretion of GLP-1 through TGR5-mTORC1 pathway in STC-1 cells. Diabetes resolves rapidly after RYGB. GLP-1 improves glycemic control in rodents and patients. Although literature has documented that postprandial secretion of GLP-1 is enhanced after RYGB, its underlying molecular mechanisms remain poorly understood. We have identified the deoxycholic acid-TGR5-mTORC1 signaling pathway as a potential mechanism by which RYGB increases GLP-1 production, thus expanding its interest as a target for the treatment of type 2 diabetes mellitus.