Reininger Laura, Rehman Muhammad H, Bouabcha Amelia, Ferragne Sarah, Tremblay Caroline, Ethier Melanie, Kimple Michelle E, Ghislain Julien, Huising Mark O, Poitout Vincent
bioRxiv. 2025 Aug 18:2025.08.15.670586. doi: 10.1101/2025.08.15.670586.
The free fatty acid receptor FFAR4 is expressed in pancreatic islets, and its activation potentiates insulin and inhibits somatostatin (SST) secretion. We investigated the mechanisms of action of FFAR4 on hormone secretion in mouse and human islets. The effects of the FFAR4 agonist Compound A (Cpd A) on insulin and SST secretion were investigated in islets from mice following ablation of delta cells, deletion of SST and deletion of the G protein Gαz (Gnaz-/-), in purified mouse beta and delta cells, in human EndoC-bH5 cells, and in human islets. Ca++ dynamics in response to Cpd A were measured in delta cells from Gnaz-/- mouse islets and in human islets. The insulinotropic effect of Cpd A was lost in delta cell-ablated and SST-deficient mouse islets and was absent in purified mouse beta cells. Gαz deletion prevented Cpd A inhibition of SST secretion but not the potentiation of insulin release. Cpd A diminished Ca++ transients in mouse delta cells, an effect that was lost in Gαz deficient islets. In human islets, FFAR4 activation increased insulin secretion and intracellular Ca++ transient independent of SST secretion. Consistent with a direct effect on beta cells, Cpd A potentiated insulin secretion in human EndoC-bH5 cells. We conclude that FFAR4 activation stimulates insulin secretion from mouse islets indirectly via Gαz-coupled inhibition of SST secretion from delta cells, while in human islets, it stimulates insulin release via a direct effect on beta cells. These key species-related differences are to be taken into account as FFAR4 is considered a potential therapeutic target for metabolic diseases.
游离脂肪酸受体FFAR4在胰岛中表达，其激活可增强胰岛素分泌并抑制生长抑素（SST）分泌。我们研究了FFAR4对小鼠和人类胰岛激素分泌的作用机制。在去除δ细胞、缺失SST和缺失G蛋白Gαz（Gnaz-/-）的小鼠胰岛、纯化的小鼠β细胞和δ细胞、人EndoC-bH5细胞以及人胰岛中，研究了FFAR4激动剂化合物A（Cpd A）对胰岛素和SST分泌的影响。在Gnaz-/-小鼠胰岛的δ细胞和人胰岛中测量了对Cpd A的Ca++动态变化。Cpd A的促胰岛素作用在去除δ细胞和缺乏SST的小鼠胰岛中消失，在纯化的小鼠β细胞中不存在。Gαz缺失阻止了Cpd A对SST分泌的抑制，但不影响胰岛素释放的增强。Cpd A减少了小鼠δ细胞中的Ca++瞬变，这种作用在缺乏Gαz的胰岛中消失。在人胰岛中，FFAR4激活增加胰岛素分泌和细胞内Ca++瞬变，与SST分泌无关。与对β细胞的直接作用一致，Cpd A增强了人EndoC-bH5细胞中的胰岛素分泌。我们得出结论，FFAR4激活通过Gαz偶联抑制δ细胞分泌SST间接刺激小鼠胰岛胰岛素分泌，而在人胰岛中，它通过对β细胞的直接作用刺激胰岛素释放。由于FFAR4被认为是代谢疾病的潜在治疗靶点，这些关键的物种相关差异需要被考虑在内。
