Bidirectional GPR119 Agonism Requires Peptide YY and Glucose for Activity in Mouse and Human Colon Mucosa

Endocrinology
I R ToughHelen M Cox

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 ...Continue Reading

References

Mar 22, 2002·British Journal of Pharmacology·Helen M Cox, Iain R Tough
Jun 30, 2006·The Journal of Pharmacology and Experimental Therapeutics·Iain R ToughHelen M Cox
Nov 11, 2009·Molecular Endocrinology·Zhi-Liang ChuJames Leonard
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Mar 2, 2016·Clinical Nutrition : Official Journal of the European Society of Parenteral and Enteral Nutrition·Nada CvijanovicTanya J Little
May 18, 2016·Journal of Diabetes Investigation·Frank Reimann, Fiona M Gribble
Aug 30, 2016·Biochemical Pharmacology·Helle A HassingMette M Rosenkilde
Sep 7, 2016·Current Opinion in Pharmacology·Helen M Cox
Dec 3, 2016·Molecular and Cellular Endocrinology·Maria HaugeThue W Schwartz
Apr 6, 2017·Cell Metabolism·Anna Sofie HustedThue W Schwartz
Jul 12, 2017·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·I R ToughH M Cox

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Citations

Apr 25, 2018·Endocrinology·Van B LuFrank Reimann
Feb 15, 2019·Nature Reviews. Endocrinology·Fiona M Gribble, Frank Reimann
Sep 22, 2018·Endocrinology·Deborah A GoldspinkFiona M Gribble
Nov 20, 2019·The American Journal of Clinical Nutrition·Christoffer MartinussenSten Madsbad
Jul 14, 2020·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·Iain R ToughHelen M Cox
Oct 27, 2018·Frontiers in Endocrinology·Silvano Paternoster, Marco Falasca
Jan 27, 2021·International Journal of Molecular Sciences·Dong-Soon Im
Apr 4, 2021·Nutrients·Van B LuFrank Reimann
Jun 26, 2021·Frontiers in Endocrinology·Rune E KuhreNatalia Petersen
Jul 9, 2021·Cellular & Molecular Biology Letters·Jianan ZhaoJinghua Peng

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