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

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 mecha