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

Abstract

BackgroundThe 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.MethodsCirculating 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.ResultsPositive 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.InterpretationDeoxycholic acid-TGR5-mTORC1 signaling contributes to the up-regulation of GLP-1 production after RYGB.

<p><em>Phocea</em>, <em>Pseudoflavonifractor</em> and <em>Lactobacillus intestinalis</em>: Three Potential Biomarkers of Gut Microbiota That Affect Progression and Complications of Obesity-Induced Type 2 Diabetes Mellitus</p>

“…60 DCA, a secondary bile acid, is positively correlated with GLP-1, which has a hypoglycemic effect. 61 Although no study yet has confirmed that bile acid can be used as an early predictor and diagnostic marker for T2DM, the results of our study supported that DCA should be further studied. DCA was also proved to be one of the endogenous ligands of Farnesoid X Receptor (FXR) that improved various dysfunctions of glucose, cholesterol, lipid, triglyceride and cholesterol metabolism.…”

Gastric Bypass Surgery Regulates Glucose Homeostasis Through the Hypothalamus

“…Microbial treatment of putrescine can produce gamma-aminobutyric acid (GABA), this is an inhibitory neurotransmitter founded in the mammalian central nervous system and is thought to stimulate intestinal cells to release GLP-1 [10]. A 6-week postoperative study demonstrated that deoxycholate-TGR5-mTORC1 signal enhancement contributes to up-regulation of GLP-1 production [11]. An increase in the density of cell population producing incretin (GLP-1 cells, GIP cells, and peptide YY immunoreactive cells) in the jejunum was observed 12 months after RYGB, which provide an anatomical explanation for the increase in GLP-1 plasma levels observed after surgery [12].…”

Mikrobiom und metabolische/bariatrische Chirurgie

“…Es konnte konklusiv Spezies-übergreifend nachgewiesen werden, dass die Serumspiegel zirkulierender biologisch aktiver Gallensäuren nach Roux-en-Y Magenbypass und Schlauchmagen erhöht sind [49,59]. Zhai et al zeigten in Mäusen und Menschen, dass es nach Magenbypass zu erhöhten Konzentrationen von Gallensäuren (insbesondere Deoxycholinsäure), einer vermehrten Expression von TGR5 im Ileum mit einer vermehrten Aktivierung des assoziierten mTORC1 Signalweges und konsekutiv zu einer vermehrten Sezernierung von GLP-1 kommt [60]. Trotzdem muss festgehalten werden, dass diese Arbeit nur Assoziationen und keine mechanistische Rolle der Gallensäuren in der vermehrten Aktivierung der L-Zellen beweist.…”