title: N-oleoyldopamine enhances glucose homeostasis through the activation of GPR119.
abstract: G protein-coupled receptor 119 (GPR119) is largely restricted to pancreatic insulin-producing beta-cells and intestinal glucagon-like peptide-1-producing L-cells. Synthetic agonists of this receptor elicit glucose-dependent release of these endocrine factors, thereby enhancing glycemic control. Oleoylethanolamide also activates GPR119, but it remains unclear whether endogenous production of this lipid modulates GPR119 activity under normal or dysglycemic conditions. We show here that a relatively diverse set of lipid amides activate GPR119. Among these, the endovallinoid N-oleoyldopamine (OLDA) stimulated cAMP accumulation in GPR119-transfected cells as effectively as oleoylethanolamide and the previously described synthetic agonist AR231453. None of these lipid amides increased cAMP in control-transfected cells or in cells transfected with a number of other G protein-coupled receptors. OLDA stimulated both cAMP accumulation and insulin release in HIT-T15 cells, which express GPR119 endogenously, and in GPR119-transfected RIN-5F cells. Oral administration of OLDA to C57bl/6 mice elicited significant improvement in glucose tolerance, whereas GPR119-deficient mice were essentially unresponsive. OLDA also acutely elevated plasma gastric inhibitory peptide levels, a known hallmark of GPR119 activation. OLDA represents a possible paracrine modulator of GPR119 in pancreatic islets, where markers of dopamine synthesis correlated well with GPR119 expression. However, no such correlation was seen in the colon. Collectively, these studies indicate that multiple, distinct classes of lipid amides, acting via GPR119, may be important modulators of glucose homeostasis.
authors.affiliation: Arena Pharmaceuticals, San Diego, California 92121, USA.
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Chu
authors.forename: Chris
authors.initials: C
authors.lastname: Carroll
authors.forename: Ruoping
authors.initials: R
authors.lastname: Chen
authors.forename: Jean
authors.initials: J
authors.lastname: Alfonso
authors.forename: Veronica
authors.initials: V
authors.lastname: Gutierrez
authors.forename: Hongmei
authors.initials: H
authors.lastname: He
authors.forename: Annette
authors.initials: A
authors.lastname: Lucman
authors.forename: Charles
authors.initials: C
authors.lastname: Xing
authors.forename: Kristen
authors.initials: K
authors.lastname: Sebring
authors.forename: Jinyao
authors.initials: J
authors.lastname: Zhou
authors.forename: Brandee
authors.initials: B
authors.lastname: Wagner
authors.forename: David
authors.initials: D
authors.lastname: Unett
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jones
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Behan
authors.forename: James
authors.initials: J
authors.lastname: Leonard
mesh_terms: D000577:Amides / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D002460:Cell Line; D006224:Cricetinae; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009928:Organ Specificity; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000577:Amides; D001786:Blood Glucose; D005227:Fatty Acids; C519854:GPR119 protein, human; C516207:Gpr119 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; C488796:N-oleoyldopamine; D004298:Dopamine