Regulation of GPR119 receptor activity with endocannabinoid-like lipids.
The GPR119 receptor plays an important role in the secretion of incretin hormones in response to nutrient consumption. We have studied the ability of an array of naturally occurring endocannabinoid-like lipids to activate GPR119 and have identified several lipid receptor agonists. The most potent receptor agonists identified were three N-acylethanolamines: oleoylethanolamine (OEA), palmitoleoylethanolamine, and linoleylethanolamine (LEA), all of which displayed similar potency in activating GPR119. Another lipid, 2-oleoylglycerol (2-OG), also activated GPR119 receptor but with significantly lower potency. Endogenous levels of endocannabinoid-like lipids were measured in intestine in fasted and refed mice. Of the lipid GPR119 agonists studied, the intestinal levels of only OEA, LEA, and 2-OG increased significantly upon refeeding. Intestinal levels of OEA and LEA in the fasted mice were low. In the fed state, OEA levels only moderately increased, whereas LEA levels rose drastically. 2-OG was the most abundant of the three GPR119 agonists in intestine, and its levels were radically elevated in fed mice. Our data suggest that, in lean mice, 2-OG and LEA may serve as physiologically relevant endogenous GPR119 agonists that mediate receptor activation upon nutrient uptake.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Samreen K
SK
Syed
Hai Hoang
HH
Bui
Lisa S
LS
Beavers
Thomas B
TB
Farb
James
J
Ficorilli
Amy K
AK
Chesterfield
Ming-Shang
MS
Kuo
Krister
K
Bokvist
David G
DG
Barrett
Alexander M
AM
Efanov
D000577:Amides; D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002460:Cell Line; D063388:Endocannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055098:Endocrine Cells / Q000187:drug effects / Q000378:metabolism; D004983:Ethanolamines / Q000037:antagonists & inhibitors / Q000378:metabolism; D005215:Fasting / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005989:Glycerides / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009829:Oleic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D009928:Organ Specificity; D010169:Palmitic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D011897:Random Allocation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013851:Thinness / Q000378:metabolism; D015854:Up-Regulation
D000577:Amides; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D004983:Ethanolamines; D005989:Glycerides; C516207:Gpr119 protein, mouse; D009829:Oleic Acids; D010169:Palmitic Acids; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; C033595:N-oleoylethanolamine; C005958:palmidrol; D052216:Glucagon-Like Peptide 1; C505247:2-oleoylglycerol