OR31-3 Role of a Novel Short Chain Fatty Acid Receptor OLFR78 in Mediating Gluco-metabolic Hormone Secretion

Abstract

Olfactory receptor OLFR78 is a G protein-coupled receptor (GPCR) which is activated by short chain fatty acids (SCFAs), especially propionate. OLFR78 is expressed in islets as well as intestinal epithelial cells. Based on these properties, we hypothesized its role in the regulation of metabolic hormone secretion. Our emerging data shows that OLFR78 signaling regulates GLP-1 secretion from murine enteroendocrine cells in vitro and ex vivo. We demonstrate that knockdown of Olfr78 through siRNA in the murine enteroendocrine cell line STC-1 results in a significant reduction in propionate-induced GLP-1 secretion. Utilizing constitutive and cyclic AMP inducible transcriptional luciferase promoters in addition to G protein pathway modulators, we further demonstrate that the signaling pathway downstream of active OLFR78 involves the activation of a Gαs subunit. As GLP-1 is an insulinotropic factor, we sought to determine the role of OLFR78 in insulin secretion and β cell mass maintenance. Using islets isolated from both wildtype and global OLFR78 knockout mice, we show that OLFR78 signaling in islets does not have a significant effect on insulin secretion. Additionally, we observed no differences in beta cell mass in wildtype versus OLFR78 knockout mice. Furthermore, no differences are observed in incretin secretion in response to oral glucose challenge between wildtype and knockout mice fed normal chow. However, ileal explants prepared from wildtype mice reveal higher secretion of GLP-1 in response to propionate challenge. These data suggest that specific activation of the receptor, rather than its presence alone, affects GLP-1 secretion. We have previously shown that the activity of other SCFA-sensing GPCRs, such as FFA2 and FFA3, are dependent on gut microbiota-derived metabolites which fluctuate with physiological stress. Similarly, we believe that the function of OLFR78 will be more evident under conditions of dietary stress, which is a crucial determinant of gut microbial activity.