Abstract
The lipid sensor G protein–coupled receptor 119 (GPR119) is highly expressed by enteroendocrine L-cells and pancreatic β-cells that release the hormones, peptide YY (PYY) and glucagonlike peptide 1, and insulin, respectively. Endogenous oleoylethanolamide (OEA) and the dietary metabolite, 2-monoacylglycerol (2-OG), can each activate GPR119. Here, we compared mucosal responses with selective, synthetic GPR119 agonists (AR440006 and AR231453) and the lipids, OEA, 2-OG, and N-oleoyldopamine (OLDA), monitoring epithelial ion transport as a readout for L-cell activity in native mouse and human gastrointestinal (GI) mucosae. We also assessed GPR119 modulation of colonic motility in wild-type (WT), GPR119-deficient (GPR119−/−), and PYY-deficient (PYY−/−) mice. The water-soluble GPR119 agonist, AR440006 (that cannot traverse epithelial tight junctions), elicited responses, when added apically or basolaterally in mouse and human colonic mucosae. In both species, GPR119 responses were PYY, Y1 receptor mediated, and glucose dependent. AR440006 efficacy matched the GI distribution of L-cells in WT tissues but was absent from GPR119−/− tissue. OEA and 2-OG responses were significantly reduced in the GPR119−/− colon, but OLDA responses were unchanged. Alternative L-cell activation via free fatty acid receptors 1, 3, and 4 and the G protein–coupled bile acid receptor TGR5 or by the melanocortin 4 receptor, was unchanged in GPR119−/− tissues. The GPR119 agonist slowed transit in WT but not the PYY−/− colon in vitro. AR440006 (intraperitoneally) slowed WT colonic and upper-GI transit significantly in vivo. These data indicate that luminal or blood-borne GPR119 agonism can stimulate L-cell PYY release with paracrine consequences and slower motility. We suggest that this glucose-dependent L-cell response to a gut-restricted GPR119 stimulus has potential therapeutic advantage in modulating insulinotropic signaling with reduced risk of hypoglycemia.
Highlights
Bidirectional G protein–coupled receptor 119 (GPR119) Agonism Requires Peptide YY and Glucose for Activity in Mouse and Human Colon Mucosa
AR440006 slowed WT colonic and upper-GI transit significantly in vivo. These data indicate that luminal or blood-borne GPR119 agonism can stimulate L-cell peptide YY (PYY) release with paracrine consequences and slower motility. We suggest that this glucose-dependent L-cell response to a gutrestricted GPR119 stimulus has potential therapeutic advantage in modulating insulinotropic signaling with reduced risk of hypoglycemia. (Endocrinology 159: 1704–1717, 2018)
The GPR119 agonists available, to date, are lipophilic and often lacking GPR119 selectivity [11]. This and other nutrient-sensing Gprotein–coupled receptor (GPCR) may be differentially targeted, and we have used native mucosal preparations that retain mucosal polarity to determine the sidedness of responses to, for example, acyl lipid mimetics, long-chain free fatty acid (LCFA)-stimulated free fatty acid receptor 1 (FFA1) and free fatty acid receptor 4 (FFA4) signaling, or L-amino acids that act via the calcium-sensing receptor [8, 10, 15, 16]
Summary
Bidirectional GPR119 Agonism Requires Peptide YY and Glucose for Activity in Mouse and Human Colon Mucosa. AR440006 (intraperitoneally) slowed WT colonic and upper-GI transit significantly in vivo These data indicate that luminal or blood-borne GPR119 agonism can stimulate L-cell PYY release with paracrine consequences and slower motility. The GPR119 agonists available, to date, are lipophilic and often lacking GPR119 selectivity [11] This and other nutrient-sensing GPCRs may be differentially targeted, and we have used native mucosal preparations that retain mucosal polarity to determine the sidedness of responses to, for example, acyl lipid mimetics, LCFA-stimulated FFA1 and free fatty acid receptor 4 (FFA4) signaling, or L-amino acids that act via the calcium-sensing receptor [8, 10, 15, 16]. A primary aim of this study was to determine the sidedness of GPR119 responses in murine and human GI mucosae using a water-soluble agonist, AR440006
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