Olfactory receptors are expressed in pancreatic β-cells and promote glucose-stimulated insulin secretion

Abstract

Olfactory receptors (ORs) mediate olfactory chemo-sensation in OR neurons. Herein, we have demonstrated that the OR chemo-sensing machinery functions in pancreatic β-cells and modulates insulin secretion. First, we found several OR isoforms, including OLFR15 and OLFR821, to be expressed in pancreatic islets and a β-cell line, MIN6. Immunostaining revealed OLFR15 and OLFR821 to be uniformly expressed in pancreatic β-cells. In addition, mRNAs of Olfr15 and Olfr821 were detected in single MIN6 cells. These results indicate that multiple ORs are simultaneously expressed in individual β-cells. Octanoic acid, which is a medium-chain fatty acid contained in food and reportedly interacts with OLFR15, potentiated glucose-stimulated insulin secretion (GSIS), thereby improving glucose tolerance in vivo. GSIS potentiation by octanoic acid was confirmed in isolated pancreatic islets and MIN6 cells and was blocked by OLFR15 knockdown. While Gαolf expression was not detectable in β-cells, experiments using inhibitors and siRNA revealed that the pathway dependent on phospholipase C-inositol triphosphate, rather than cAMP-protein kinase A, mediates GSIS potentiation via OLFR15. These findings suggest that the OR system in pancreatic β-cells has a chemo-sensor function allowing recognition of environmental substances obtained from food, and potentiates insulin secretion in a cell-autonomous manner, thereby modulating systemic glucose metabolism.

Inactivation of SREBP-1a Phosphorylation Prevents Fatty Liver Disease in Mice: Identification of Related Signaling Pathways by Gene Expression Profiles in Liver and Proteomes of Peroxisomes

“…Several OLFR have been identified in non-olfactory tissues, and these interact with metabolism, maybe in “sniffing” available metabolite concentrations for metabolic adaptation and regulation of energy metabolism. These include OLFR that act on hepatic TG or FFA metabolism, adipose tissue FA lipolysis, or beta cell insulin secretion and further evidence is just emerging [ 32 , 33 , 34 ]. Although the biological relevance is unclear, our study confirms an earlier observation of increased OLFR gene expression in fatty liver of an adipose tissue transplantation model [ 35 ].…”

Fatty Acid Increases cAMP-dependent Lactate and MAO-B-dependent GABA Production in Mouse Astrocytes by Activating a GαsProtein-coupled Receptor

“…In addition, a recent study revealed that ORs recognize SCFAs and MCFAs in many non-olfactory tissues [ 17 ]. Representative examples are Olfr78 [ 15 ], Olfr544 [ 46 ], and Olfr15 [ 47 48 ], which recognize SCFAs, dicarboxylic MCFAs, and MCFAs, respectively. A further study is required to identify the GPCR that recognizes free MCFAs in astrocytes.…”

Mechanisms of octanoic acid potentiation of insulin secretion in isolated islets

“…Olfactory receptors, especially OLFR15, have been recently implicated in the potentiating effect of OA on GSIS in insulinoma MIN6 cells. 35 The down-stream mechanism of olfactory receptor on insulin secretion was likely through IP3 receptor pathways. 35 When Sur1 -/islets were treated with the IP3 receptor inhibitor 2-ABP (50 µM), the OAinduced increase in [Ca 2+ ] i in Sur1 -/islets was abolished ( Figure 5(c)).…”