GPR119, a Major Enteroendocrine Sensor of Dietary Triglyceride Metabolites Coacting in Synergy With FFA1 (GPR40).

Triglycerides (TGs) are among the most efficacious stimulators of incretin secretion; however, the relative importance of FFA1 (G Protein-coupled Receptor [GPR] 40), FFA4 (GPR120), and GPR119, which all recognize TG metabolites, ie, long-chain fatty acid and 2-monoacylglycerol, respectively, is still unclear. Here, we find all 3 receptors to be highly expressed and highly enriched in fluorescence-activated cell sorting-purified GLP-1 and GIP cells isolated from transgenic reporter mice. In vivo, the TG-induced increase in plasma GIP was significantly reduced in FFA1-deficient mice (to 34%, mean of 4 experiments each with 8-10 animals), in GPR119-deficient mice (to 24%) and in FFA1/FFA4 double deficient mice (to 15%) but not in FFA4-deficient mice. The TG-induced increase in plasma GLP-1 was only significantly reduced in the GPR119-deficient and the FFA1/FFA4 double deficient mice, but not in the FFA1, and FFA4-deficient mice. In mouse colonic crypt cultures the synthetic FFA1 agonists, TAK-875 stimulated GLP-1 secretion to a similar extent as the prototype GLP-1 secretagogue neuromedin C; this, however, only corresponded to approximately half the maximal efficiency of the GPR119 agonist AR231453, whereas the GPR120 agonist Metabolex-209 had no effect. Importantly, when the FFA1 agonist was administered on top of appropriately low doses of the GPR119 agonist, a clear synergistic, ie, more than additive, effect was observed. It is concluded that the 2-monoacylglycerol receptor GPR119 is at least as important as the long-chain fatty acid receptor FFA1 in mediating the TG-induced secretion of incretins and that the 2 receptors act in synergy, whereas FFA4 plays a minor if any role.

GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes.

The expression of short-chain fatty acid receptors GPR41/FFAR3 and GPR43/ free fatty acid receptor 2 (FFAR2) was studied in the gastrointestinal tract of transgenic monomeric red fluorescent protein (mRFP) reporter mice. In the stomach free fatty acid receptor 3 (FFAR3)-mRFP was expressed in a subpopulation of ghrelin and gastrin cells. In contrast, strong expression of FFAR3-mRFP was observed in all cholecystokinin, glucose-dependent insulinotropic peptide (GIP), and secretin cells of the proximal small intestine and in all glucagon-like peptide-1 (GLP-1), peptide YY, and neurotensin cells of the distal small intestine. Throughout the colon and rectum, FFAR3-mRFP was strongly expressed in the large population of peptide YY and GLP-1 cells and in the neurotensin cells of the proximal colon. A gradient of expression of FFAR3-mRFP was observed in the somatostatin cells from less than 5% in the stomach to more than 95% in the rectum. Substance P-containing enterochromaffin cells displayed a similar gradient of FFAR3-mRFP expression throughout the small intestine. Surprisingly, FFAR3-mRFP was also expressed in the neuronal cells of the submucosal and myenteric ganglia. Quantitative PCR analysis of fluorescence-activated cell sorting (FACS) purified FFAR3-mRFP positive cells confirmed the coexpression with the various peptide hormones as well as key neuronal marker proteins. The FFAR2-mRFP reporter was strongly expressed in a large population of leukocytes in the lamina propria of in particular the small intestine but surprisingly only weakly in a subpopulation of enteroendocrine cells. Nevertheless, synthetic ligands specific for either FFAR3 or FFAR2 each released GLP-1 from colonic crypt cultures and the FFAR2 agonist mobilized intracellular Ca²âº in FFAR2 positive enteroendocrine cells. It is concluded that FFAR3-mRFP serves as a useful marker for the majority of enteroendocrine cells of the small and large intestine and that FFAR3 and FFAR2 both act as sensors for short-chain fatty acids in enteroendocrine cells, whereas FFAR3 apparently has this role alone in enteric neurons and FFAR2 in enteric leukocytes.