Ileal TGR5-mTORC1 Signaling Contributes To The Increment Of GLP-1 Production After RYGB Surgery

Objective:Roux-en-Y gastric bypass surgery(RYGB)is effective in the treatment of obesity and related chronic metabolic diseases such as type 2 diabetes mellitus,but its application is limited by surgical risk and complications.Therefore,it is of great clinical significance to study the use of drugs instead of surgery in the treatment of obesity and diabetes mellitus.In this study,we explored gastrointestinal fuel sensor mTOR to change the synthesis and secretion of gastrointestinal hormone Glucagon-Like Peptide-1(GLP-1)after RYGB operation,which could provide a theoretical basis for screening the surgical alternative therapy "pharmaceutical gastric bypass".Methods:The activity of TGR5 and mTORC1 in ileum and the synthesis and secretion of GLP-1 were observed after RYGB operation and exogenous change of mTOR activity after RYGB in obese type 2 diabetic mice induced by high-fat diets.The ileum tissue samples from non-diabetic patients,obese type 2 diabetic patients and obese type 2diabetic patients 1 year after RYGB operation were collected,and the activities of TGR5,mTORC1 and the expression of GLP-1 were detected.Gene silencing(mTOR siRNA and TGR5 siRNA)and drug treatment(Deoxycholic acid,DCA)were used to investigate the effects of mTORC1 and TGR5 on GLP-1 synthesis and secretion in mouse intestinal secretin tumor cell line STC-1.Results:RYGB increased 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 TGR5 expression and GLP-1 synthesis induced by RYGB in diet-induced obese type 2 diabetic mice.GLP-1 production and ileal TGR5-mTORC1 signaling were positively correlated with plasma DCA in mice.Treatment of STC-1cells 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 the interaction between mTOR-regulatory-associated protein of mechanistic target of rapamycin(Raptor)and TGR5 in STC-1 cells.Conclusion:Ileal TGR5-mTORC1 signaling contributes to the increment of GLP-1 production after RYGB surgery.