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
复制标题
雷帕霉素复合物 1 信号传导的武田 G 蛋白偶联受体 5 机制靶点有助于 Roux-en-Y 胃旁路手术后胰高血糖素样肽 1 产量的增加
DOI：
10.1016/j.ebiom.2018.05.026
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发表时间：
2018-06-01
期刊：
影响因子：
11.1
通讯作者：
Xu, Geyang
中科院分区：
文献类型：
--
作者：
Zhai, Hening;Li, Zhi;Xu, Geyang
背景资料：Roux-en-Y胃旁路术（RYGB）增加胰高血糖素样肽-1（GLP-1）分泌的机制仍不完全确定。在此，我们研究了TGR 5-mTORC 1信号转导是否介导RYGB诱导的小鼠和人类GLP-1产生的改变。方法：在有或没有RYGB手术的瘦或肥胖雄性C57 BL/6小鼠中，以及在正常血糖受试者、肥胖2型糖尿病患者在RYGB前后，测定循环胆汁酸、TGR 5-mTORC 1信号转导、GLP-1合成和分泌。在本研究中，在能量状态变化期间，观察到循环胆汁酸、雷帕霉素复合物1（mTORC 1）信号传导的回肠机械靶点和GLP-1之间的正相关性。RYGB增加小鼠和人类受试者的循环胆汁酸、回肠Takeda G蛋白偶联受体5（TGR 5）和mTORC 1信号传导活性以及GLP-1产生。雷帕霉素抑制回肠mTORC 1信号传导显著减弱了RYGB诱导的瘦小鼠和饮食诱导的肥胖小鼠胆汁酸分泌、TGR 5表达和GLP-1合成的刺激。GLP-1产生和回肠TGR 5-mTORC 1信号传导与小鼠血浆脱氧胆酸（DCA）呈正相关。用DCA处理STC-1细胞刺激GLP-1的产生。这种效应与TGR 5-mTORC 1信号传导的显著增强相关。siRNA敲低mTORC 1或TGR 5可消除DCA诱导的GLP-1合成增强。DCA增加了STC-1细胞中雷帕霉素机制靶点mTOR调节相关蛋白（Raptor）与TGR 5之间的相互作用。解释：脱氧胆酸-TGR 5-mTORC 1信号通路有助于RYGB后GLP-1产生的上调。(C)2018爱思唯尔出版社
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. (C) 2018 Published by Elsevier B.V.