title: Modulation of Glucagon-like Peptide-1 (GLP-1) Potency by Endocannabinoid-like Lipids Represents a Novel Mode of Regulating GLP-1 Receptor Signaling.
abstract: Glucagon-like peptide-1 (GLP-1) analogs are approved for treatment of type 2 diabetes and are in clinical trials for disorders including neurodegenerative diseases. GLP-1 receptor (GLP-1R) is expressed in many peripheral and neuronal tissues and is activated by circulating GLP-1. Other than food intake, little is known about factors regulating GLP-1 secretion. Given a normally basal circulating level of GLP-1, knowledge of mechanisms regulating GLP-1R signaling, which has diverse functions in extrapancreatic tissues, remains elusive. In this study, we found that the potency of GLP-1, not exendin 4, is specifically enhanced by the endocannabinoid-like lipids oleoylethanolamide (OEA) and 2-oleoylglycerol but not by stearoylethanolamide (SEA) or palmitoylethanolamide. 9.2 μM OEA enhances the potency of GLP-1 in stimulating cAMP production by 10-fold but does not affect its receptor binding affinity. OEA and 2-oleoylglycerol, but not SEA, bind to GLP-1 in a dose-dependent and saturable manner. OEA but not SEA promoted GLP-1(7-36) amide to trypsin inactivation in a dose-dependent and saturable manner. Susceptibility of GLP-1(7-36) amide to trypsin inactivation is increased 40-fold upon binding to OEA but not to SEA. Our findings indicate that OEA binds to GLP-1(7-36) amide and enhances the potency that may result from a conformational change of the peptide. In conclusion, modulating potency of GLP-1 by physiologically regulated endocannabinoid-like lipids allows GLP-1R signaling to be regulated spatiotemporally at a constant basal GLP-1 level.
authors.affiliation: From the Genomic Research Center and.
authors.forename: Yu-Hong
authors.initials: YH
authors.lastname: Cheng
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Mei-Shang
authors.initials: MS
authors.lastname: Ho
authors.affiliation: From the Genomic Research Center and.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Huang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Ying-Ting
authors.initials: YT
authors.lastname: Chou
authors.affiliation: From the Genomic Research Center and bmkxk@ibms.sinica.edu.tw.
authors.forename: Klim
authors.initials: K
authors.lastname: King
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D063388:Endocannabinoids; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D005989:Glycerides / Q000378:metabolism*; D006801:Humans; D009829:Oleic Acids / Q000378:metabolism*; D051381:Rats; D018027:Receptors, Glucagon / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D063388:Endocannabinoids; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D005989:Glycerides; D009829:Oleic Acids; D018027:Receptors, Glucagon; C488250:oleoylethanolamide; D052216:Glucagon-Like Peptide 1; C505247:2-oleoylglycerol; D000242:Cyclic AMP
keywords: G protein-coupled receptor (GPCR); bioluminescence resonance energy transfer (BRET); endocannabinoid; lipid; signaling