GPR119 as a fat sensor

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GPR119 as a fat sensor Harald S. Hansen1, Mette M. Rosenkilde2, Jens J. Holst3,4 and Thue W. Schwartz2,4 1

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark 2 Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, the Panum Institute, University of Copenhagen, 2200 Copenhagen, Denmark 3 Department of Biomedical Sciences, Faculty of Health and Medical Sciences, the Panum Institute, University of Copenhagen, 2200 Copenhagen, Denmark 4 NovoNordisk Foundation Center for Basal Metabolic Research, Faculty of Health and Medical Sciences, the Panum Institute, University of Copenhagen, 2200 Copenhagen, Denmark

The GPR119 receptor is expressed predominantly in pancreatic b 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. 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 [1–3]. GLP-1 is a potent insulin-releasing and appetite-suppressing hormone, and GLP-1 analogs in clinical practice lower blood glucose and body weight. Type 2 diabetes is associated with early loss of pancreatic b-cell sensitivity as well as loss of intestinal GLP-1 release in response to dietary carbohydrates, and especially in obese individuals [4]. Thus, GPR119 is a highly topical drug target for treating diabetes and obesity (Box 1). GPR119 is predominantly expressed in the pancreas and the intestine, where it is found on b cells and on Corresponding author: Hansen, H.S. ([email protected]).

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enteroendocrine K- (GIP) and L-cells (GLP-1, -2 and PYY), respectively [5–8], although the distinction between K- and L-cells secreting different incretins may not be as clear as generally imagined [9,10]. In the pancreas, activation of GPR119 increases glucose-stimulated insulin release via the formation of cAMP, suggesting that the receptor operates through activation of Gas [5,11,12]. In the enteroendocrine cells, activation of GPR119 stimulates release of the incretins GLP-1 and glucose-dependent insulinotropic peptide (GIP) [13]. GPR119-mediated insulin secretion from the pancreas is glucose-dependent, whereas GPR119-mediated GLP-1 secretion from the enteroendocrine cells appears to be glucose-independent [14]. GPR119-null mice appear normal and retain a normal insulin release in response to glucose and GLP-1, whereas the GLP-1-stimulatory effect of proposed GPR119 agonists such as N-oleoyl-dopamine (OLDA) is lost [13]. GPR119null mice fed a low-fat diet showed normal plasma glucose and lipids, but they had lower body-weight and lower postprandial plasma levels of GLP-1. Food-stimulated GLP-1 release was attenuated in these mice, suggesting a physiological role of GPR119 in mediating GLP-1 secretion in response to food intake [15]. Postprandial levels of GLP-1 – but not GIP – were also attenuated in GPR119null mice fed a high-fat diet [15]. This suggests that one or more dietary components or metabolites from fat may be physiological activators of GPR119 and thereby regulators of GLP-1 release [15]. 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 demonstrated only in vitro, and which of them, if any, is connected to dietinduced release of GLP-1 (which is attenuated in GPR119null mice) is unknown [15]. Various dietary components have been found to stimulate intestinal release of GLP-1, for example glucose, amino acids, proteins, carbohydrate

0165-6147/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tips.2012.03.014 Trends in Pharmacological Sciences, July 2012, Vol. 33, No. 7

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Box 1. Small-molecule synthetic GPR119 agonists Owing to the supposedly fairly selective expression of GPR119 in the endocrine pancreas this receptor was targeted by the pharmaceutical industry at a very early stage, in other words long before its molecular pharmacology, cell biology and true physiological importance were elucidated – and before its endogenous ligands were identified [67,68]. Thus, the first GPR119 agonists were patented as enhancers of insulin secretion by the Yamanushi team already in 2001–2003, closely followed by similar patent applications from Arena and Prosidion. In 2007 Chu and coworkers published the prototype GPR119 agonist AR231453 (Figure I) as a potent, glucose-dependent stimulator of insulin secretion having an efficacy similar to GLP-1, and they demonstrated in GPR119-deficient mice that its action was dependent upon the receptor [5]. GPR119 gained even more attention as a drug target when Overton and coworkers showed evidence that small-molecule synthetic GPR119 agonists could decrease food intake and reduce body-weight gain in rats on high-fat diet [17] – an effect which, however, has been difficult to confirm with other high-potency and selective GPR119 agonists [67,68]. Shortly thereafter, Chu and coworkers expanded the potential of GPR119 agonists considerably when they found that the receptor is expressed in enteroendocrine cells and demonstrated that AR231453 stimulated cAMP accumulation and GLP-1 secretion in GLUTag cells, and furthermore increased plasma levels of both GLP-1 and GIP during a glucose challenge [6]. Moreover, by use of the GLP-1 antagonist exendine(9–36) it was shown that the ability of GPR119 agonists to improve glucose

O

N N O

tolerance was partly dependent upon GLP-1, and that this effect could be improved by combination with a DPP-IV inhibitor [6]. Thus, strong preclinical evidence indicated that a GPR119 agonist should be able to provide all the beneficial effects of GLP-1 – through increased release of the endogenous hormone – while at the same time being a glucose-dependent insulin secretagog [67,68]. Accordingly, the expectations for this novel class of drugs were very high when they entered clinical trials. Unfortunately, very limited information is yet available from these trials in the form of scientific publications. Meeting reports and press releases suggest that the first-generation GPR119 agonists have not lived up to expectations. In collaboration with Johnson & Johnson, Arena took first APD668 and subsequently APD597 into clinical trials and although they did observe positive effects on meal-associated glucose excursions, they apparently did not obtain meaningful improvements of glucose tolerance in type 2 diabetic patients. Similar results were reported by GlaxoSmithKline from their internal GPR119 program at the American Diabetes Association meeting in 2011. Moreover, recently Sanofi-Aventis returned an inlicensed GPR119 project to Metabolex in the same way that Johnson & Johnson returned their joint GPR119 project to Arena. Although no results have yet been reported from multiple-dose clinical studies in type 2 diabetes, it appears that the currently available GPR119 agonists, which are all of somewhat similar structure (Figure I), have provided disappointing results in Phase II clinical trials – despite encouraging appropriate in vitro and in vivo preclinical efficacies.

O

O

O N

N

N O

N

N

N O

N N

N

N N O

N

N

NO2

N N

O

S

N

O

OMe N

NH

N

N N

F

NH

Arena (AR231453)

O

N

F

N SO2 M e

N

O

MeO2S

Arena (APD668)

MeO2S

Arena (APD597)

F SO2 Me

Prosidion (PSN-?)

SO 2Me

GSK (GSK1292263)

N N N N

Metabolex (MBX-2982)

TRENDS in Pharmacological Sciences

Figure I. Structures of six selected synthetic GPR119 agonists. To the left are shown the prototype GPR119 agonist, the tool compound AR231453 from Arena followed by their first two clinical candidates APD668 and its successor APD597. The structure of the clinical candidate PSN-821 from Prosidion has not been revealed, but ‘PSN-?’ is indicated a representative compound from their extensive patent literature. GlaxoSmithKline has taken GSK-1292263 and Metabolex has taken MBX-2982 into Phase II clinical trials.

and triacylglycerol [18,19], but in general the underlying molecular mechanisms have not been identified. 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 concentrations of

3–4 mM, depending on the size of the meal and the amount of the phosphatidylcholine released from the gall bladder [21]. LysoPC is also a normal constituent of human plasma reaching a concentration around 100 mM [22], but is mostly bound to albumin and various lipoproteins. Of the investigated lysophospholipids, lysoPC appears to be the most potent activator of GPR119 (Table 1). Oleoyl-containing lysoPC has been found to activate GPR119 by several groups [11,17,23–26], but not by all [13], although oleoyl-containing lysoPC seems to be the most potent of the investigated lysoPC species. Several groups have observed bell-shaped dose–response curves for lysoPC, possibly due to detergent-like toxic effects of 375

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Table 1. Endogenous agonists for GPR119 Compound 1-Oleoyl-lysophosphatidylcholine (18:1-lysoPC)

1-Palmitoyl-lysophosphatidylcholine (16:0-lysoPC) 1-Stearoyl-lysophosphatidylcholine (18:0-lysoPC) Lysophosphatidylethanolamine 1-Oleoyl-lysophosphatidylethanolamine Lysophosphatidylinositol Lysophosphatidylserine Lysophosphatidic acid Sphingosylphosphorylcholine Oleic acid

Oleamide Oleoylethanolamide (OEA)

Palmitoylethanolamide (PEA) Linoleoylethanolamide (LEA) Anandamide N-Oleoyl-dopamine (OLDA) N-Arachidonoyl-dopamine N-Oleoyl-tyrosine 2-Oleoyl glycerol (2OG) 2-Linoleoyl glycerol (2LG) 2-Palmitoyl glycerol (2PG) 2-Arachidonoyl glycerol 1-Oleoyl glycerol 1-Linoleoyl glycerol 5-Hydroxy-eicosapentaenoic acid (5-HEPE)

EC50 (mM) 1.5

Ref. [11]

>30 NR 9.0 a 1.6

[17] [13] [23] [11]

2.1 a 3.3

[23] [11]

5.7 12 a 5.7 >30 >30 >30 >30 NR >1000 4.5 3.2 4.4 0.20 0.84 0.56 >30 NA 3.2 NR NR 2.5 12 11 NA 2.8 36 0.03–3

[11] [23] [11] [11] [11] [11] [11] [13] [23] [13] [17] [13] [23] [23] [23] [17] [23] [13] [13] [13] [23] [23] [23] [23] [23] [23] [24]

NR, no response; NA, not applicable. a

Under our assay conditions, higher concentrations of lysophospholipid were toxic to the cells, and the EC50 was therefore extrapolated from the stimulation at lower concentrations.

this lipid at higher concentrations. Because lysoPC is a lipid that is sparsely water-soluble, its effects in cell culture will be dependent on the concentration of free lysoPC, which is dependent upon cell density and albumin concentration, as also reported for other lipids such as ceramide [27]. Thus, it is not surprising that different EC50 values are obtained for the same lipid agonist by different groups in different cell-culture systems (Table 1). Because phosphatidylcholine is released from the gall bladder during a meal in relatively large amounts [28], it is possible that the rapidly formed intestinal lysoPC contributes to the meal-associated, GPR119-mediated GLP-1 release. However, bile acids present in bile may also cause a release of GLP-1 through activation of the recently identified bile acid receptor, TGR5, another member of the seventransmembrane receptor family [29] which is expressed by L-cells. Without appropriate pharmacological receptor tools such as selective antagonists it is difficult to determine the 376

relative contribution of these different ligands and receptors to the meal-induced GLP-1 release – along with the various other dietary components. 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 the proposed endogenous or naturally occurring agonists, OEA is the most potent (Table 1). In addition, several other non-oleic acid-containing acylethanolamides activate GPR119 in vitro and could potentially all act as endogenous agonists for GPR119. The endocannabinoid anandamide (with a 20-carbon acyl group) is not an agonist, suggesting that the GPR119 activity of acylethanolamides is due to the N-acyl group of 16–18 carbon atoms and 0–2 double bonds (Table 1). However, the anorectic mechanism of OEA may not involve GPR119, because OEA injected into GPR119-null mice retains its anorectic effect [15]. OEA and other acylethanolamides are rather minor constituents of some vegetable food items, but their levels in food items are far too low to have any food-related GPR119-stimulatory effect or other anorectic effect [33]. OEA and other acylethanolamides are produced in intestinal cells, where they are thought to contribute to the regulation of food intake mainly via PPARa activation and via vagal signals to brain appetite centers [31,32,34–36]. These findings indicate that OEA and possibly other anorectic acylethanolamides could function in an autocrine or paracrine manner to stimulate gut hormone release. Dietary fat is known to stimulate GLP-1 release [37], but – importantly – dietary fat lowers instead of increases intestinal levels of OEA and other acylethanolamides in a dose-dependent manner [36,38]. An intraluminal intestinal infusion of oleic acid leads to a small increase in the level of OEA in the enterocytes [39], but dietary studies with fat intake have shown that the overall level of all GPR119-stimulating acylethanolamines in the enterocytes decreases [36,38], although there may be a small relative increase in the specific acylethanolamide that can be formed from the corresponding fatty acid found in the dietary fat. Thus, olive oil administration (rich in oleic acid) results in a small relative increase in OEA, palm oil (rich in palmitic acid) in a small relative increase in PEA, and safflower oil (rich in linoleic acid) in a small relative increase in LEA [38]. The conclusion is that the acylethanolamines cannot be direct mediators of dietary, fat-induced GPR119 activation and GLP-1 release. OEA is also produced in the rat pancreas where the level increased upon food deprivation [40]. This speaks against local OEA formation having a stimulatory effect on insulin secretion via activation of GPR119, because insulin secretion decreases upon food deprivation. Thus, there is little evidence for activation of GPR119 by endogenous OEA in the pancreas.

Review Oleamide (Table 1) and erucamide have been reported to be endogenous lipid metabolites and are often associated thematically with the acylethanolamides. However, recent studies suggest that they may derive from plastics during sample preparations [41,42], and their biological significance has been questioned [43]. Although biosynthetic pathways for oleamide have been suggested [44,45], the role of oleamide as a physiological endogenous compound and its role as an endogenous agonist for GPR119 are still questionable. 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 have been detected in brain tissue, including the amino-containing compounds dopamine, serotonin, serine, alanine, glycine, g-amino-butyric acid, taurine, and ethanolamine [47]. Whereas the acylethanolamides are formed from a precursor phospholipid molecule, many of the N-acyl-amino compounds – including OLDA – may be formed in a cytochrome c-catalyzed reaction where the acyl group of acyl-CoA is transferred to the amino compound in question [48]. Such a reaction may take place in post mortem brain tissue, raising the question whether these N-acyl adducts are true endogenous compounds or whether they are formed only in cases of tissue injury and cell death. Thus, at present it is questionable whether OLDA is a true endogenous compound and a physiologically relevant agonist for GPR119. 5-Hydroxy-eicosapentaenoic acid (5-HEPE) Recently, 5-HEPE and oleoyl-containing-lysoPC were found to stimulate insulin release in MIN6 cells dosedependently 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 items, for example fish oil [49]. The corresponding arachidonic acid derivative, 5-hydroxy-eicosatetraenoic acid, did not stimulate insulin release from MIN6 cells [24]. Thus, for rodents on a normal chow and humans having a Western diet, 5-HEPE seems to be of little relevance as an endogenous agonist for GPR119 because it is present only in extremely low amounts. In an extensive review discussing dietary fat and prevention of type 2 diabetes it was concluded that dietary long-chain n-3 fatty acids do not appear to improve insulin sensitivity or glucose metabolism in humans, as opposed to dietary (n-6) fatty acids [50]. Thus, this gives little room for 5-HEPE as a relevant endogenous GPR119 agonist, and irrespective of whether an individual has an intake of long-chain (n-3) fatty acids or not.

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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 GLP1 release induced by intraduodenal infusion of oleate [52]. This suggests that dietary fat, hydrolyzed to fatty acids, can stimulate GLP-1 release through a GPR40-mediated release of CCK. GPR120 is another fatty acid receptor found in the intestine, the activation of which has been shown to stimulate GLP-1 release [53]. Thus, a-linolenic acid and docosahexaenoic acid were found to be full GPR120 agonists in vitro, but the receptor was only poorly activated by oleic acid and palmitic acid, indicating that it is primarily activated by (n-3) fatty acids [53]. In GPR120-null mice, a high-fat diet (rich in oleic acid) induces insulin resistance as in wild-type mice. However, the beneficial effect of a high-fat diet containing a high percentage of fish oil as regards insulin resistance was lost in the GPR120-deficient mice [54], suggesting that GPR120 mediates the beneficial effects of (n-3) fatty acids in vivo. Thus, GPR120 is probably not involved in olive oilinduced GLP-1 release in humans. Oleic acid has been reported to stimulate GLP-1 release in mice via activation of PKCz [55], but it is unclear whether this also takes place in humans. 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 fat will result in the formation of approximately 40 g 2-monoacylglycerol per day in the small intestine, and the levels of monoacylglycerol can rise to 15 mM in the intestinal lumen after ingestion of a meal containing 34 g fat [57]. It is unknown how much of this 15 mM is present as the monomer or is associated with lipid vesicles. 2-Monoacylglycerols have been shown to stimulate GPR119 in transfected cell lines, and although less potent that OEA (Table 1) [23], the mere quantity of 2-monoacylglycerols formed in the intestine makes them a good physiological candidate for mediating fat-induced GLP-1 release in the intestine. The endocannabinoid 2-arachidonoyl glycerol did not stimulate GPR119. 2-OG appears to be more potent than 2-palmitoyl glycerol (2-PG), and this may explain the observation that dietary fat having mainly oleic acid in the sn-2 position results in higher plasma GLP-1 and GIP responses in humans during a meal as compared to dietary fat predominantly containing palmitic acid in the sn-2 position [56,58,59]. Generally, most vegetable fats are enriched with oleic acid in the sn-2 position whereas dairy fat and lard are enriched with palmitic acid in the sn-2 position 377

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O

Food lipids

O

O

O

O

Triglycerides

O

Pancreatic lipase

O OH

O OH

O

Long-chain fatty acids

OH O HO

Luminal

2-Oleoyl glycerol (2-OG)

GPR40 GPR120

GPR119 O C N H

OH

Paracrine

?

OEA

cAMP

(NAE) O

NAPE O R3 C N H

R1 C O CH2

O

O H C O C R2 O P O CH2

PPARα TRPV1

OH

Phospholipids

Gut hormones

PYY GLP-2 GLP-1 Paracrine Endocrine functions Neuronal functions activation TRENDS in Pharmacological Sciences

Figure 1. Schematic overview of the generation and putative luminal versus paracrine action of two types of natural, endogenous ligands for GPR119 in the enteroendocrine system. Several lipid metabolites with various affinities for GPR119 are generated by enzymes in the tissue and are proposed to act as local paracrine modulators of GPR119 activity – here represented by OEA generated from phospholipids in, for example, neighboring enterocytes (Figure 2 and Table 1 for other proposed paracrine GPR119 ligands). Whether each of these in fact functions as a physiological regulator of GPR119 depends on whether they are actually generated in physiologically meaningful amounts. The anorectic effect of OEA may be mediated by the receptors PPARa and TRPV1. Of particular importance for GPR119 expressed in the enteroendocrine system are 2-monoacylglycerols – here represented by 2-oleoyl glycerol (2-OG) – generated in very large amounts in the gut lumen from dietary fat (triglycerides) through cleavage by pancreatic lipase. By sensing 2-monoacylglycerols, GPR119 probably acts as a major ‘fat sensor’ in the enteroendocrine system regulating the expression and secretion of gut hormones such as GLP-1 and -2 and PYY from the L-cell – as indicated – but also, for example, GIP. These hormones then regulate several metabolic functions in the body through endocrine, paracrine and neuronal mechanisms.

[56]. 1-Monoacylglycerols are also able to activate GPR119 (Table 1), but are rapidly degraded by pancreatic lipase, whereas 2-monoacylglycerols are formed by this enzyme. Thus, 1-monoacylglycerols are not expected to be found in large amounts in the lumen of the small intestine. A dose of 2 g 2-OG delivered via a duodenal tube to healthy volunteers resulted in a significantly increased level of GLP-1 in plasma within 25 min following the administration [23]. As a control, an equimolar amount of 1.54 g oleic acid – a relatively low dose of fatty acid – did not stimulate GLP-1 378

release, demonstrating that the GLP-1-releasing activity of 2-OG on a molar basis is more potent than that of oleic acid. There was no difference in plasma CCK levels between groups. Along with GLP-1, plasma levels of GIP were also increased, indicating that GPR119 activation may also stimulate GIP release in humans. The finding that 2-monoacylglycerol stimulates GLP-1 release may also explain the increased GLP-1 response upon fat-feeding of mice that lack the enzyme acyl-CoA:monoacylglycerol acyltransferase-2 (MGAT2-KO) [60]: in these mice

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the luminal level of 2-monoacylglycerol may have been increased. Okawa et al. [61] did not observe increased GLP-1 release in MGAT2-KO mice upon fat-feeding, but they did observe increased GLP-1 release in mice deficient in acyl-CoA:diacylglycerol acyltransferase-1 [61] – lack of which may also lead to increased intestinal levels of 2monoacylglycerol. Inhibition of triacylglycerol/chylomicron formation in the enterocytes in rats in vivo resulted in increased GLP-1 release [62], a response that also may be mediated by increased luminal content of both 2-monoacylglycerol and fatty acids that accumulate in the lumen because of inhibited flux through the enterocyte (Figure 1). Thus, it seems likely that the meal-related formation of 2-monoacylglycerols acting on GPR119 during fat-digestion is responsible for an at least part of the GLP-1 response. It appears possible that oleic acid via CCK release may stimulate GLP-1 release in humans although only in fairly high doses, but whether lysoPC also contributes to meal-induced GLP-1 release is not clear. Furthermore, it is plausible that bile acids may also contribute via activation of TGR5. Further studies must clarify the individual contributions of the different luminal lipids, and antagonists for GPR119 (Figure 2) and other enteroendocrine chemosensors will be valuable tools in these studies. Finally, the effect of 2-OG needs to be tested in GPR119-deficient mice.

GPR119 in the endocrine pancreas GPR119 is highly expressed in b 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 b cells is involved in some way in stimulating insulin release [63]. Thus, knockout of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), respectively, in pancreas results in impaired glucose-induced insulin secretion [64,65]. ATGL hydrolyses triacylglycerol to diacylglycerol and a fatty acid and HSL then hydrolyses diacylglycerol to 2-monoacylglycerol and a fatty acid, and it was speculated that an unidentified triacylglycerol metabolite may serve as an amplification signal in glucose-induced insulin secretion [63–65]. This unidentified metabolite could be fatty acid or acyl-CoA, but it might also be 2-monoacylglycerol potentiating insulin secretion via GPR119. If this is the case, unknown mechanisms probably compensate for the missing contribution of GPR119 to insulin secretion in GPR119-null mice. Lipoprotein lipase is also sn1,sn3-specific and generates 2-monoacylglycerol and fatty acids during its lipolytic action on chylomicrons and very-low-density lipoprotein [66]. Whether this 2-monoacylglycerol can stimulate GPR119 in pancreatic islets is not known.

Paracrine function

Luminal function

(tissue generated)

(from dietary fat and bile) HO

HO

O OH

Me3N

O

NH O

HO OEA HO

O P O O

O 2-OG O

OH

O

18:1-lysoPC NH O

OH

OH O

OLDA 5-HEPE

TRENDS in Pharmacological Sciences

Figure 2. Structures of some of the major lipid metabolites proposed to be naturally occurring, endogenous GPR119 agonist ligands. Four of the GPR119 agonists are oleic acid derivatives: oleoylethanolamide (OEA), N-oleoyl-dopamine (OLDA), 1-oleoyl-lysophosphatidylcholine (18:1-lysoPC) and 2-oleoyl glycerol (2-OG), the last is 5-hydroxyeicosapentaenoic acid (5-HEPE). As indicated they are all believed to potentially be lipid metabolites generated by various enzymes within the tissue where they are expected to act locally as agonists on GPR119 in an autocrine or paracrine fashion (Figure 1). However, 2-OG is mainly generated in large amounts from dietary triglycerides through the action of pancreas lipase and 18:1-lysoPC can be generated from PCs in the bile; both metabolites are proposed to act predominantly from the luminal side on GPR119 expressed on the apical sensory extension of the enteroendocrine cells (Figure 1).

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Review 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 mealassociated 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 2monoacylglycerol might stimulate insulin release through activation of GPR119, but this has to be investigated further using, for example, GPR119 antagonists as pharmacological tools. Much basic research concerning the molecular pharmacology and biology of GPR119 is required before we can exploit the potential of this receptor as a drug target with second-generation GPR119 agonists (Box 1). It will be essential to understand the interaction of GPR119 with various endogenous lipid metabolites generated locally in or around the target cell and how this may affect the function of drug compounds. 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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