An Acetate-Specific GPCR, FFAR2, Regulates Insulin Secretion
An Acetate-Specific GPCR, FFAR2, Regulates Insulin Secretion
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DOI：
10.1210/me.2015-1007
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发表时间：
2015-07-01
影响因子：
--
通讯作者：
Layden, Brian T.
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文献类型：
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作者：
Priyadarshini, Medha;Villa, Stephanie R.;Layden, Brian T.
G蛋白偶联受体已被充分描述为有助于葡萄糖刺激的胰岛素分泌（GSIS）的调节。短链脂肪酸敏感G蛋白偶联受体，游离脂肪酸受体2（FFAR 2），在胰腺β细胞中表达，在啮齿动物中，其表达在胰岛素抵抗期间发生变化。因此，我们探索了FFAR 2在调节GSIS中的作用。首先，在体内评估野生型和Ffar 2（-/-）小鼠的表型，我们观察到在正常或高脂肪饮食的葡萄糖稳态方面没有差异，在高血糖钳夹期间，Ffar 2（-/-）小鼠的胰岛素分泌有轻微的显著缺陷。在离体胰岛素分泌研究中，我们观察到在高葡萄糖条件下，相对于野生型胰岛，Ffar 2（-/-）胰岛的GSIS减少。此外，在乙酸盐（FFAR 2的主要内源性配体）存在下，我们观察到GSIS的FFAR 2依赖性增强，而FFAR 2特异性激动剂导致GSIS的增强或抑制，我们发现这分别是通过G α（q/11）或G α（i/o）的选择性信号传导引起的。最后，在人胰岛的离体胰岛素分泌研究中，我们观察到乙酸盐和FFAR 2激动剂在人FFAR 2处引起与在小鼠FFAR 2处不同的信号传导特性。综上所述，我们的研究表明，FFAR 2信号通过不同的G蛋白途径发生，可以选择性地增强或抑制小鼠胰岛中的GSIS。此外，我们已经确定了小鼠和人FFAR 2对选择性激动剂的反应的重要差异，并且我们建议在继续研究FFAR 2作为新的2型糖尿病靶点时考虑这些差异。
G protein-coupled receptors have been well described to contribute to the regulation of glucose-stimulated insulin secretion (GSIS). The short-chain fatty acid-sensing G protein-coupled receptor, free fatty acid receptor 2 (FFAR2), is expressed in pancreatic beta-cells, and in rodents, its expression is altered during insulin resistance. Thus, we explored the role of FFAR2 in regulating GSIS. First, assessing the phenotype of wild-type and Ffar2(-/-) mice in vivo, we observed no differences with regard to glucose homeostasis on normal or high-fat diet, with a marginally significant defect in insulin secretion in Ffar2(-/-) mice during hyperglycemic clamps. In ex vivo insulin secretion studies, we observed diminished GSIS from Ffar2(-/-) islets relative to wild-type islets under high-glucose conditions. Further, in the presence of acetate, the primary endogenous ligand for FFAR2, we observed FFAR2-dependent potentiation of GSIS, whereas FFAR2-specific agonists resulted in either potentiation or inhibition of GSIS, which we found to result from selective signaling through either G alpha(q/11) or G alpha(i/o), respectively. Lastly, in ex vivo insulin secretion studies of human islets, we observed that acetate and FFAR2 agonists elicited different signaling properties at human FFAR2 than at mouse FFAR2. Taken together, our studies reveal that FFAR2 signaling occurs by divergent G protein pathways that can selectively potentiate or inhibit GSIS in mouse islets. Further, we have identified important differences in the response of mouse and human FFAR2 to selective agonists, and we suggest that these differences warrant consideration in the continued investigation of FFAR2 as a novel type 2 diabetes target.