Modulation of Glucagon-like Peptide (GLP)-1 Potency by Endocannabinoid-like Lipids Represents A Novel Mode of Regulating GLP-1 Receptor Signaling.

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 (Ex-4) is specifically enhanced by endocannabinoid-like lipids oleoylethanolamide (OEA), 2-oleoylglycerol (2-OG) but not by stearoylethanolamide (SEA) or palmitoylethanolamide (PEA). 9.2 uM of OEA enhance the potency of GLP-1 in stimulating cAMP production by 10-fold, but does not affect its receptor binding affinity. OEA and 2-OG but not SEA binds to GLP-1 in a dose dependent and saturable manner. OEA but not SEA promoted GLP-1 (7-36) amide to trypsin inactivation in dose dependent and saturable manner. Susceptibility of GLP-1 (7-36) amide to trypsin inactivation is increased by 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 which 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 constant basal GLP-1 level.
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