Lipid derivatives activate GPR119 and trigger GLP-1 secretion in primary murine L-cells
Lipid derivatives activate GPR119 and trigger GLP-1 secretion in primary murine L-cells
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DOI：
10.1016/j.peptides.2015.06.012
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发表时间：
2016-03-01
期刊：
影响因子：
3
通讯作者：
Reimann, Frank
中科院分区：
文献类型：
--
作者：
Hodge, Daryl;Glass, Leslie L.;Reimann, Frank
目的/假设：胰高血糖素样肽-1 （Glucagon-like peptide-1, GLP-1）是胰高血糖素原衍生的一种肠促胰岛素激素，由肠l细胞释放，以葡萄糖依赖的方式增加胰岛素分泌。GPR119是一种存在于l细胞中的脂质衍生物受体，被认为在检测膳食脂肪中起作用。本研究旨在表征原代小鼠l细胞对GPR119激动作用的反应，并评估GPR119在检测摄入脂质的重要性。方法：用GPR119配体刺激小鼠原代细胞培养，测定GLP-1的分泌。脂质灌胃后，测定胰高血糖素原表达细胞和对照组缺乏GPR119小鼠血浆GLP-1水平。利用表达胰高血糖素前启动子驱动cAMP FRET传感器的转基因小鼠，在单个原代l细胞中测量细胞内cAMP对GPR119激动剂的反应。结果：l细胞特异性敲除GPR119显著降低脂质灌胃后血浆GLP-1水平。GPR119配体在结肠原代上皮培养物中以GPR119依赖的方式触发GLP-1分泌，但在上小肠中效果较差。GPR119激动剂使大约70%的结肠l细胞和50%的小肠l细胞的cAMP升高。结论/解释：GPR119配体强烈增强结肠培养物中GLP-1的释放，反映了高比例的结肠l细胞对GPR119激动剂表现出cAMP反应。上小肠对gpr119的依赖性较低。在体内，l细胞中的GPR119在口腔脂质触发的GLP-1分泌中起关键作用。(C) 2015年作者。Elsevier Inc.出版。
Aims/hypothesis: Glucagon-like peptide-1 (GLP-1) is an incretin hormone derived from proglucagon, which is released from intestinal L-cells and increases insulin secretion in a glucose dependent manner. GPR119 is a lipid derivative receptor present in L-cells, believed to play a role in the detection of dietary fat. This study aimed to characterize the responses of primary murine L-cells to GPR119 agonism and assess the importance of GPR119 for the detection of ingested lipid.Methods: GLP-1 secretion was measured from murine primary cell cultures stimulated with a panel of GPR119 ligands. Plasma GLP-1 levels were measured in mice lacking GPR119 in proglucagon-expressing cells and controls after lipid gavage. Intracellular cAMP responses to GPR119 agonists were measured in single primary L-cells using transgenic mice expressing a cAMP FRET sensor driven by the proglucagon promoter.Results: L-cell specific knockout of GPR119 dramatically decreased plasma GLP-1 levels after a lipid gavage. GPR119 ligands triggered GLP-1 secretion in a GPR119 dependent manner in primary epithelial cultures from the colon, but were less effective in the upper small intestine. GPR119 agonists elevated cAMP in similar to 70% of colonic L-cells and 50% of small intestinal L-cells.Conclusions/interpretation: GPR119 ligands strongly enhanced GLP-1 release from colonic cultures, reflecting the high proportion of colonic L-cells that exhibited cAMP responses to GPR119 agonists. Less GPR119-dependence could be demonstrated in the upper small intestine. In vivo, GPR119 in L-cells plays a key role in oral lipid-triggered GLP-1 secretion. (C) 2015 The Authors. Published by Elsevier Inc.