GPR119, a Major Enteroendocrine Sensor of Dietary Triglyceride Metabolites Coacting in Synergy With FFA1 (GPR40)
GPR119, a Major Enteroendocrine Sensor of Dietary Triglyceride Metabolites Coacting in Synergy With FFA1 (GPR40)
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DOI：
10.1210/en.2016-1334
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发表时间：
2016-12-01
期刊：
影响因子：
4.8
通讯作者：
Schwartz, Thue W.
中科院分区：
文献类型：
--
作者：
Ekberg, Jeppe H.;Hauge, Maria;Schwartz, Thue W.
甘油三酯（TG）是肠促胰岛素分泌最有效的刺激物之一;然而，FFA 1（G蛋白偶联受体[GPR] 40）、FFA 4（GPR 120）和GPR 119（它们都分别识别TG代谢物，即长链脂肪酸和2-单酰基甘油）的相对重要性仍不清楚。在这里，我们发现所有3种受体在从转基因报告小鼠分离的荧光激活细胞分选纯化的GLP-1和GIP细胞中高度表达和高度富集。在体内，TG诱导的血浆GIP增加在FFA 1缺陷小鼠（至34%，4次实验的平均值，每次8-10只动物）、GPR 119缺陷小鼠（至24%）和FFA 1/FFA 4双缺陷小鼠（至15%）中显著降低，但在FFA 4缺陷小鼠中未降低。TG诱导的血浆GLP-1升高仅在GPR 119缺陷和FFA 1/FFA 4双缺陷小鼠中显著降低，但在FFA 1和FFA 4缺陷小鼠中未显著降低。在小鼠结肠隐窝培养物中，合成的FFA 1激动剂TAK-875刺激GLP-1分泌的程度与原型GLP-1促分泌素神经介肽C相似;然而，这仅相当于GPR 119激动剂AR 231453最大效力的约一半，而GPR 120激动剂Metabolex-209无影响。重要的是，当在适当低剂量的GPR 119激动剂的基础上施用FFA 1激动剂时，观察到明显的协同作用，即超过累加作用。它的结论是，2-单酰基甘油受体GPR 119是至少一样重要的长链脂肪酸受体FFA 1在介导的TG诱导的肠促胰岛素分泌和2受体的协同作用，而FFA 4起着次要的作用，如果有的话。
Triglycerides (TGs) are among the most efficacious stimulators of incretin secretion; however, the relative importance of FFA1 (G Protein-coupled Receptor [GPR] 40), FFA4 (GPR120), and GPR119, which all recognize TG metabolites, ie, long-chain fatty acid and 2-monoacylglycerol, respectively, is still unclear. Here, we find all 3 receptors to be highly expressed and highly enriched in fluorescence- activated cell sorting-purified GLP-1 and GIP cells isolated from transgenic reporter mice. In vivo, the TG-induced increase in plasma GIP was significantly reduced in FFA1-deficient mice (to 34%, mean of 4 experiments each with 8-10 animals), in GPR119-deficient mice (to 24%) and in FFA1/FFA4 double deficient mice (to 15%) but not in FFA4-deficient mice. The TG-induced increase in plasma GLP-1 was only significantly reduced in the GPR119-deficient and the FFA1/FFA4 double deficient mice, but not in the FFA1, and FFA4-deficient mice. In mouse colonic crypt cultures the synthetic FFA1 agonists, TAK-875 stimulated GLP-1 secretion to a similar extent as the prototype GLP-1 secretagogue neuromedin C; this, however, only corresponded to approximately half the maximal efficiency of the GPR119 agonist AR231453, whereas the GPR120 agonist Metabolex-209 had no effect. Importantly, when the FFA1 agonist was administered on top of appropriately low doses of the GPR119 agonist, a clear synergistic, ie, more than additive, effect was observed. It is concluded that the 2-monoacylglycerol receptor GPR119 is at least as important as the long-chain fatty acid receptor FFA1 in mediating the TG-induced secretion of incretins and that the 2 receptors act in synergy, whereas FFA4 plays a minor if any role.