Regulation of GPR119 receptor activity with endocannabinoid-like lipids

Abstract

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.GPR119; linoleoylethanolamine; oleoylethanolamine; 2-oleoylglycerol GUT HORMONES, SUCH AS glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY), are peptides whose secretion from enteroendocrine intestinal cells is stimulated by the intake of nutrients. Released peptides signal to enhance nutrient metabolism and limit further nutrient consumption. These peptides play a crucial role in the regulation of glucose and lipid metabolism by stimulating insulin secretion, inhibiting glucagon secretion, improving insulin sensitivity, slowing gastric emptying, increasing satiety, and reducing food intake (12,31

Sustained wash-resistant receptor activation responses of GPR119 agonists

“…GPR119 demonstrates a highly localized pattern of expression within the gastrointestinal tract and pancreas (Lan et al, 2009;Lauffer et al, 2009;Soga et al, 2005) consistent with a role in metabolic function. Endogenous agonists for GPR119 are lipids such as oleoylethanolamine and 2-oleoyl glycerol, further supporting this role (Cornall et al, 2013;Hansen et al, 2011;Syed et al, 2012). Indeed, stimulation of GPR119 is strongly linked with glucose homoeostasis with a direct effect on insulin release from pancreatic β-cells, as well as an indirect effect on insulin signalling via glucagon-like peptide 1 (GLP-1) release from enteroendocrine cells (Chu et al, , 2007Soga et al, 2005).…”

“…GPR119 is a class A G protein-coupled receptor (GPCR) that signals predominantly through cAMP via the stimulatory G-protein (Gα s ) (Lauffer et al, 2009;Syed et al, 2012). GPR119 demonstrates a highly localized pattern of expression within the gastrointestinal tract and pancreas (Lan et al, 2009;Lauffer et al, 2009;Soga et al, 2005) consistent with a role in metabolic function.…”

Endocannabinoid system and pregnancy

“…Cumulative evidence suggests the existence of a putative third type of cannabinoid receptor ('CB3'), called GPR55 (Ryberg et al 2007, Sharir & Abood 2010. Interestingly, and adding complexity to the pharmacology of cannabinoids, it has been shown that these compounds might elicit response in other receptors, such as transient receptor potential vanilloid 1 (TRPV1), peroxisome proliferatoractivated receptors (PPARs) and GPR119 (Huang et al 2002, Sun et al 2006, Syed et al 2012.…”

Analysis of ECs and related compounds in plasma: artifactual isomerization and ex vivo enzymatic generation of 2-MGs

“…Analogously, for the 2-monoacylglycerol (MG) series, there are also homologs such as 2-oleoylglycerol (OG) and 2-linoleoylglycerol (LG). Most of these molecules do not directly bind to CB receptors but may enhance/modify the actions of ECs (entourage effect) ( 6 ) or display biological activities related to their interactions with other receptors such as GPR119 (OEA, POEA, LEA, 2-OG) ( 7,8 ), transient receptor potential vanilloid type 1 (TRPV1) (OEA), GPR55 (PEA), or PPAR-␣ (OEA) ( 9 ). Finally, two putative ECs, N-eicosapentaenoyl ethanolamide (EPEA) and N-docosahexaenoyl ethanolamide (DHEA), derived from the n-3 polyunsaturated fatty acids, are able to bind with low affi nity to the CB1 and CB2 receptors and may have biological signifi cance in the brain ( 10,11 ).…”