Objective: Maintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free fatty-acid receptor 4 (FFAR4/GPR120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (alpha, beta, and delta cells) to the insulinotropic and glucagonotropic effects of GPR120 remains unclear. As gpr120 mRNA is enriched in somatostatin-secreting delta cells, we hypothesized that GPR120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release. Methods: Glucose tolerance tests were performed in mice after administration of the selective GPR120 agonist Compound A. Insulin, glucagon and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and/or pharmacological (Compound A and AZ-13581837) GPR120 agonists. The effect of Compound A on hormone secretion was tested further in islets isolated from mice with global or somatostatin cell-specific knockout of gpr120. Gpr120 expression was assessed in pancreatic sections by RNA in situ hybridization. Cyclic AMP (cAMP) and calcium dynamics in response to pharmacological GPR120 agonists were measured specifically in alpha, beta and delta cells in intact islets using cAMPER and GCaMP6 reporter mice, respectively. Results: Acute exposure to Compound A increased glucose tolerance and circulating insulin and glucagon levels in vivo. Endogenous and/or pharmacological and GPR120 agonists reduced somatostatin secretion in isolated islets and concomitantly demonstrated dose-dependent potentiation of glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion. Gpr120 was enriched in delta cells. Pharmacological GPR120 agonists reduced cAMP and calcium levels in delta cells but increased these signals in alpha and beta cells. Compound A-mediated inhibition of somatostatin secretion was insensitive to pertussis toxin. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of gpr120 and was partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin. Conclusions: Inhibitory GPR120 signaling in delta cells contributes to both insulin and glucagon secretion in part via mitigating somatostatin release.

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三角洲细胞中的游离脂肪酸受体4抑制信号调节小鼠胰岛激素的分泌

目的：维持葡萄糖稳态需要精确调节内分泌胰腺的激素分泌。游离脂肪酸受体4（FFAR4 / GPR120）是一种G蛋白偶联受体，其在Langerhans胰岛中的激活可促进胰岛素和胰高血糖素的分泌，并抑制生长抑素的分泌。但是，尚不清楚单个胰岛细胞类型（α，β和δ细胞）对GPR120的促胰岛素和促胰激素作用的贡献。由于gpr120 mRNA在分泌促生长素抑制素的三角洲细胞中富集，我们假设GPR120激活通过抑制促生长素抑制素释放来刺激胰岛素和胰高血糖素的分泌。方法：在给予选择性GPR120激动剂化合物A后，对小鼠进行了葡萄糖耐量试验。在对内源性（ω-3多不饱和脂肪酸）和/或药理性（化合物A和AZ-13581837）GPR120激动剂起反应的离体小鼠胰岛的静态孵育中，测定了胰高血糖素和生长抑素的分泌。在从具有gpr120整体或生长抑素细胞特异性敲除的小鼠的胰岛中进一步测试了化合物A对激素分泌的作用。通过RNA原位杂交评估胰腺切片中的Gpr120表达。分别使用cAMPER和GCaMP6报告基因小鼠，分别在完整胰岛中的α，β和δ细胞中分别测量了响应于药理GPR120激动剂的环AMP（cAMP）和钙动力学。结果：化合物A的急性暴露增加了体内的葡萄糖耐量和体内胰岛素和胰高血糖素的水平。内源性和/或药理和GPR120激动剂可减少离体胰岛中生长抑素的分泌，并伴随剂量依赖性地增强葡萄糖刺激的胰岛素分泌和精氨酸刺激的胰高血糖素分泌。Gpr120富含delta细胞。药理学上的GPR120激动剂降低了delta细胞中的cAMP和钙水平，但增加了alpha和beta细胞中的这些信号。化合物A介导的生长抑素分泌抑制对百日咳毒素不敏感。具有gpr120全局或生长抑素细胞特异性缺失的小鼠的胰岛中完全没有化合物A对激素分泌的作用，而通过环生长抑素阻断生长抑素受体信号传导后，部分地降低了化合物A对激素分泌的作用。结论：