Free-fatty acid receptor 4 inhibitory signaling in delta cells regulates islet hormone secretion in mice

ObjectiveMaintenance 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 (, {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. MethodsGlucose tolerance tests were performed in mice after administration of the selective Gpr120 agonist Cpd A. Gpr120 mRNA levels were assessed in pancreatic section by RNA in situ hybridization. Insulin, glucagon and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous ({omega}-3 polyunsaturated fatty acids) and pharmacological (Compound A and AZ-13581837) Gpr120 agonists. The effect of Compound A on hormone secretion was tested in islets isolated from mice with global or somatostatin cell-specific knockout (KO) of Gpr120. Calcium and cAMP dynamics in response to pharmacological Gpr120 agonists were measured in islets isolated from , {beta} and {delta} cell-specific GCaMP6 and CAMPER reporter mice, respectively. ResultsAcute exposure to Compound A increased glucose tolerance and circulating insulin and glucagon levels in vivo. Both pharmacological and endogenous Gpr120 agonists dose-dependently potentiated glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion and concomitantly reduced somatostatin secretion in isolated islets. 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. Gpr120 agonists reduced forskolin-stimulated cAMP levels in {delta} cells, but did not evoke calcium signaling in islet cells. ConclusionsThis study supports a key contribution of inhibitory Gpr120-Gi/o signaling in {delta}-cells in both insulin and glucagon secretion in part via mitigating somatostatin release.