TY - JOUR
T1 - Bidirectional GPR119 agonism requires peptide YY and glucose for activity in mouse and human colon mucosa
AU - Tough, Iain R
AU - Forbes, Sarah
AU - Herzog, Herbert
AU - Jones, Robert M
AU - Schwartz, Thue W
AU - Cox, Helen M
PY - 2018/4/1
Y1 - 2018/4/1
N2 - The lipid sensor G protein'coupled receptor 119 (GPR119) is highly expressed by enteroendocrine Lcells and pancreatic b-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 Noleoyldopamine (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 (GPR1192/2), and PYY-deficient (PYY2/2) 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 efficacymatched the GI distribution of L-cells inWT tissues butwas absent fromGPR1192/2 tissue.OEA and 2-OG responses were significantly reduced in the GPR1192/2 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 GPR1192/2 tissues. The GPR119 agonist slowed transit in WT but not the PYY2/2 colon in vitro. AR440006 (intraperitoneally) slowedWT colonic and upper-GI transit significantly in vivo. These data indicate that luminal or blood-borne GPR119 agonismcan stimulate L-cell 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.
AB - The lipid sensor G protein'coupled receptor 119 (GPR119) is highly expressed by enteroendocrine Lcells and pancreatic b-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 Noleoyldopamine (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 (GPR1192/2), and PYY-deficient (PYY2/2) 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 efficacymatched the GI distribution of L-cells inWT tissues butwas absent fromGPR1192/2 tissue.OEA and 2-OG responses were significantly reduced in the GPR1192/2 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 GPR1192/2 tissues. The GPR119 agonist slowed transit in WT but not the PYY2/2 colon in vitro. AR440006 (intraperitoneally) slowedWT colonic and upper-GI transit significantly in vivo. These data indicate that luminal or blood-borne GPR119 agonismcan stimulate L-cell 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.
U2 - 10.1210/en.2017-03172
DO - 10.1210/en.2017-03172
M3 - Journal article
C2 - 29471473
SN - 0013-7227
VL - 159
SP - 1704
EP - 1717
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 4
ER -