Long-chain fatty acids (LCFAs) are not only energy sources but also serve as signaling molecules. GPR120, an LCFA receptor, plays key roles in maintaining metabolic homeostasis. However, whether endogenous ligand-GPR120 circuits exist and how such circuits function in pancreatic islets are unclear. Here, we found that endogenous GPR120 activity in pancreatic δ-cells modulated islet functions. At least two unsaturated LCFAs, oleic acid (OA) and linoleic acid (LA), were identified as GPR120 agonists within pancreatic islets. These two LCFAs promoted insulin secretion by inhibiting somatostatin secretion and showed bias activation of GPR120 in a model system. Compared with OA, LA exerted higher potency in promoting insulin secretion, which is dependent on β-arrestin2 function. Moreover, GPR120 signaling was impaired in the diabetic db/db model, and replenishing OA and LA improved islet function in both the db/db and streptozotocin-treated diabetic models. Consistently, the administration of LA improved glucose metabolism in db/db mice. Collectively, our results reveal that endogenous LCFA-GPR120 circuits exist and modulate homeostasis in pancreatic islets. The contributions of phenotype differences caused by different LCFA-GPR120 circuits within islets highlight the roles of fine-tuned ligand-receptor signaling networks in maintaining islet homeostasis.

中文翻译：

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内源性脂质-GPR120 信号传导在不同程度上调节胰岛稳态。

长链脂肪酸 (LCFA) 不仅是能量来源，而且还充当信号分子。GPR120 是一种 LCFA 受体，在维持代谢稳态中起关键作用。然而，是否存在内源性配体-GPR120 回路以及这些回路如何在胰岛中发挥作用尚不清楚。在这里，我们发现胰腺 δ 细胞中的内源性 GPR120 活性调节胰岛功能。至少两种不饱和 LCFA，油酸 (OA) 和亚油酸 (LA)，被鉴定为胰岛内的 GPR120 激动剂。这两种 LCFA 通过抑制生长抑素分泌来促进胰岛素分泌，并在模型系统中显示出 GPR120 的偏向激活。与 OA 相比，LA 在促进胰岛素分泌方面发挥了更高的效力，这取决于 β-arrestin2 的功能。此外，GPR120 信号在糖尿病 db/db 模型中受损，在 db/db 和链脲佐菌素治疗的糖尿病模型中，补充 OA 和 LA 可改善胰岛功能。一致地，LA 的施用改善了 db/db 小鼠的葡萄糖代谢。总的来说，我们的研究结果表明，内源性 LCFA-GPR120 电路存在并调节胰岛的稳态。由胰岛内不同 LCFA-GPR120 回路引起的表型差异的贡献突出了微调配体受体信号网络在维持胰岛稳态中的作用。