Review
GPR119 as a fat sensor

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The GPR119 receptor is expressed predominantly in pancreatic β cells and in enteroendocrine cells. It is a major target for the development of anti-diabetic drugs that through GPR119 activation may stimulate both insulin and GLP-1 release. GPR119 can be activated by oleoylethanolamide and several other endogenous lipids containing oleic acid: these include N-oleoyl-dopamine, 1-oleoyl-lysophosphatidylcholine, generated in the tissue, and 2-oleoyl glycerol generated in the gut lumen. Thus, the well-known stimulation of GLP-1 release by dietary fat is probably not only mediated by free fatty acids acting through, for example, GPR40, but is also probably mediated in large part through the luminal formation of 2-monoacylglycerol acting on the ‘fat sensor’ GPR119. In the pancreas GPR119 may also be stimulated by 2-monoacylglycerol generated from local turnover of pancreatic triacylglycerol. Knowledge about the endogenous physiological ligands and their mode of interaction with GPR119 will be crucial for the development of efficient second-generation modulators of this important drug target.

Section snippets

GPR119 is found in pancreas and intestine; pharmacological activation results in increased insulin and GLP-1 release in these respective tissues

G protein-coupled receptors are a family of cell-surface proteins serving as sensors for various extracellular stimuli such as hormones, neurotransmitters, light, odorants and nutrients. One of these receptors, GPR119, has attracted pharmacological interest as a target for the development of small-molecule drugs that can both stimulate insulin release from the pancreas and glucagon-like peptide-1 (GLP-1) release from the intestine 1, 2, 3. GLP-1 is a potent insulin-releasing and

Several endogenous lipids are agonists for GPR119

Initially, GPR119 was classified as an orphan receptor [16], but in 2005 lysophospholipids containing oleic acid, palmitic acid or stearic acid were found to have agonist activity [11] and in 2006 the anorectic lipid oleoylethanolamide (OEA) was also shown to be a potent and efficacious GPR119 agonist [17]. Later, several other endogenous lipid metabolites were shown to be GPR119 agonists in transfected cell lines (Table 1). However, for all these lipids (Table 1) the agonist activity has been

Lysophospholipids

Lysophospholipids are generated from their corresponding phospholipid after release of a fatty acid, catalyzed by the enzyme phospholipase A2. Thus, lysophosphatidylcholine (lysoPC) is generated from phosphatidylcholine. In the intestinal lumen, lysoPC may derive from either phosphatidylcholine in the diet or from phosphatidylcholine secreted with the bile. Dietary intake of phosphatidylcholine by humans is in the order of 150 mg/day [20], and in the human small intestinal lumen lysoPC can reach

Oleoylethanolamide and other acylamides

Oleoylethanolamide (OEA) is an endogenous lipid known to have anorectic properties when fed to rodents [30], injected intraperitoneally into rodents [31], or when formed endogenously in rodent intestinal cells in vivo by adenoviral vector-induced overexpression of the enzyme generating OEA [32]. OEA has been identified as a full agonist for GPR119 in various cell lines [17], and intraluminally injected OEA has been reported to stimulate GLP-1 release in mice via GPR119 activation [25]. Of all

N-Oleoyl-dopamine (OLDA)

Chu et al. found that several lipids including OLDA have agonistic activity for transiently expressed GPR119 [13]. OLDA was first isolated together with other N-acyl-dopamines from bovine cerebral striatum and was found to stimulate calcium influx in vanilloid receptor-transfected HEK 293 cells [46]. Peripheral sites of OLDA synthesis have not been described. OLDA belongs to a large group of N-acyl-amino compounds that have been isolated in the recent years. More than 40 different compounds

5-Hydroxy-eicosapentaenoic acid (5-HEPE)

Recently, 5-HEPE and oleoyl-containing-lysoPC were found to stimulate insulin release in MIN6 cells dose-dependently and apparently via GPR119 activation because GPR119-targeting siRNA treatment attenuated the effect, suggesting that 5-HEPE is an endogenous GPR119 agonist [24]. 5-HEPE can be formed by a 5-lipoxygenase from eicosapentanoic acid, a long-chain (n-3)-fatty acid, but it is rarely present in the tissues of laboratory animals or humans unless they have a large intake of marine food

Fatty acids

Dietary fat, largely triacylglycerol, is known to stimulate GLP-1 release, an effect that has be ascribed to activation of GPR120 or GPR40 by fatty acids formed in the intestinal lumen during lipid digestion. Thus, dietary fat can be hydrolyzed to fatty acids that can activate GPR40 and cause CCK release as seen in mice [51]. In human studies, an antagonist of the CCK-A receptor attenuated the GLP-1 release induced by intraduodenal infusion of oleate [52]. This suggests that dietary fat,

2-Oleoyl glycerol (2-OG) and other 2-monoacylglycerols

Fat digestion in the gastrointestinal tract does not only produce fatty acids. Pancreas lipase is sn1,sn3-specific for the hydrolysis of triacylglycerol, thereby resulting in the formation of 2 molecules of fatty acid and one molecule of 2-monoacylglycerol, all of which are absorbed and used for triacylglycerol regeneration in the enterocyte [56] (Figure 1). Only a minor part of the 2-monoacylglycerol formed is hydrolyzed to glycerol and fatty acid [56]. Therefore, a daily consumption of 100 g

GPR119 in the endocrine pancreas

GPR119 is highly expressed in β cells of the pancreatic islets, but glucose-induced insulin secretion is not impaired in GPR119-null mice, suggesting that GPR119 is not essential for insulin release. However, this needs to be carefully examined because compensatory mechanisms may exist. Several studies have implied that triacylglycerol turnover in β cells is involved in some way in stimulating insulin release [63]. Thus, knockout of hormone-sensitive lipase (HSL) and adipose triglyceride lipase

Concluding remarks

Several endogenous and food-associated lipid metabolites can activate GPR119, but in the intestine 2-monoacylglycerol seems to be the most important endogenous meal-associated agonist, and is likely to be responsible for at least part of the dietary fat-mediated GLP-1 release. Free fatty acids, lysoPC and bile acids may also be physiologically meaningful regulators of GLP-1 release. In the pancreas there is some evidence that locally produced 2-monoacylglycerol might stimulate insulin release

Acknowledgments

This work was supported by UNIK: Food, Fitness, and Pharma for Health and Diseases (www.foodfitnesspharma.ku). The UNIK project is supported by the Danish Ministry of Science, Technology, and Innovation, and by The Novo Nordisk Foundation Center for Basic Metabolic Research at University of Copenhagen, which is based on an unconditional grant from the Novo Nordisk Foundation.

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