Free fatty acid receptor 4 agonists stimulate insulin secretion via different mechanisms in mouse versus human islets

Reininger, L.; Rehman, M. H.; Bouabcha, A.; Ferragne, S.; Tremblay, C.; Ethier, M.; Kimple, M. E.; Ghislain, J.; Huising, M. O.; Poitout, V.

doi:10.1101/2025.08.15.670586

bioRxiv · 10.1101/2025.08.15.670586

Free fatty acid receptor 4 agonists stimulate insulin secretion via different mechanisms in mouse versus human islets

Reininger, L.·Rehman, M. H.·Bouabcha, A.·Ferragne, S.·Tremblay, C.·Ethier, M.·Kimple, M. E.·Ghislain, J.·Huising, M. O.·Poitout, V.

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Abstract

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 Gz (Gnaz-/-), in purified mouse {beta} and {delta} cells, in human EndoC-{beta}H5 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. Gz 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 Gz 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-{beta}H5 cells. We conclude that FFAR4 activation stimulates insulin secretion from mouse islets indirectly via Gz-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. STRUCTURED ABSTRACTO_ST_ABSObjectivesC_ST_ABSThe free fatty acid receptor FFAR4 (GPR120) is expressed in the murine islet where its activation promotes insulin and glucagon and inhibits somatostatin (SST) secretion. However, its precise mechanism of action in different islet cells is still unknown, and potential species-related differences have not been explored. This study was aimed to address three questions: 1-What is the relative importance of {delta} cells and SST in the insulinotropic effect of FFAR4 in mouse islets? 2-Which G protein does FFAR4 couple to in mouse {delta} cells? 3-Does FFAR4 stimulate insulin secretion by similar mechanisms in mouse and human islets? MethodsThe 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 Gz (Gnaz-/-), in purified mouse {beta} and {delta} cells, in human EndoC-{beta}H5 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 using adenovirally-transduced Ca++ reporters. ResultsThe insulinotropic effect of Cpd A was lost in {delta} cell-ablated and SST-deficient mouse islets and was absent in purified mouse {beta} cells. Gz deletion diminished Ca++ transients in mouse {delta} cells, prevented Cpd A inhibition of SST secretion but did not inhibit the potentiation of insulin release. In human islets, FFAR4 activation increased insulin secretion and intracellular Ca++ transient without affecting SST secretion. Consistent with a direct effect on {beta} cells, Cpd A potentiated insulin secretion in human EndoC-{beta}H5 cells. ConclusionFFAR4 activation stimulates insulin secretion from mouse islets indirectly via Gz-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.

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Reininger, L., Rehman, M. H., Bouabcha, A., Ferragne, S., Tremblay, C., Ethier, M., Kimple, M. E., Ghislain, J., Huising, M. O., Poitout, V.. 2025-08-18. Free fatty acid receptor 4 agonists stimulate insulin secretion via different mechanisms in mouse versus human islets. https://doi.org/10.1101/2025.08.15.670586

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