Oleoylethanolamide Stimulates Lipolysis by Activating the Nuclear Receptor Peroxisome Proliferator-activated Receptor α (PPAR-α)

Abstract

Amides of fatty acids with ethanolamine (FAE) are biologically active lipids that participate in a variety of biological functions, including the regulation of feeding. The polyunsaturated FAE anandamide (arachidonoylethanolamide) increases food intake by activating G protein-coupled cannabinoid receptors. On the other hand, the monounsaturated FAE oleoylethanolamide (OEA) reduces feeding and body weight gain by activating the nuclear receptor PPAR-α (peroxisome proliferator-activated receptor α). In the present report, we examined whether OEA can also influence energy utilization. OEA (1–20 μm) stimulated glycerol and fatty acid release from freshly dissociated rat adipocytes in a concentration-dependent and structurally selective manner. Under the same conditions, OEA had no effect on glucose uptake or oxidation. OEA enhanced fatty acid oxidation in skeletal muscle strips, dissociated hepatocytes, and primary cardiomyocyte cultures. Administration of OEA in vivo (5 mg kg–1, intraperitoneally) produced lipolysis in both rats and wild-type mice, but not in mice in which PPAR-α had been deleted by homologous recombination (PPAR-α–/–). Likewise, OEA was unable to enhance lipolysis in adipocytes or stimulate fatty acid oxidation in skeletal muscle strips isolated from PPAR-α mice. The synthetic PPAR-α agonist Wy-14643 produced similar effects, which also were dependent on the presence of PPAR-α. Subchronic treatment with OEA reduced body weight gain and triacylglycerol content in liver and adipose tissue of diet-induced obese rats and wild-type mice, but not in obese PPAR-α–/– mice. The results suggest that OEA stimulates fat utilization through activation of PPAR-α and that this effect may contribute to its anti-obesity actions. Amides of fatty acids with ethanolamine (FAE) are biologically active lipids that participate in a variety of biological functions, including the regulation of feeding. The polyunsaturated FAE anandamide (arachidonoylethanolamide) increases food intake by activating G protein-coupled cannabinoid receptors. On the other hand, the monounsaturated FAE oleoylethanolamide (OEA) reduces feeding and body weight gain by activating the nuclear receptor PPAR-α (peroxisome proliferator-activated receptor α). In the present report, we examined whether OEA can also influence energy utilization. OEA (1–20 μm) stimulated glycerol and fatty acid release from freshly dissociated rat adipocytes in a concentration-dependent and structurally selective manner. Under the same conditions, OEA had no effect on glucose uptake or oxidation. OEA enhanced fatty acid oxidation in skeletal muscle strips, dissociated hepatocytes, and primary cardiomyocyte cultures. Administration of OEA in vivo (5 mg kg–1, intraperitoneally) produced lipolysis in both rats and wild-type mice, but not in mice in which PPAR-α had been deleted by homologous recombination (PPAR-α–/–). Likewise, OEA was unable to enhance lipolysis in adipocytes or stimulate fatty acid oxidation in skeletal muscle strips isolated from PPAR-α mice. The synthetic PPAR-α agonist Wy-14643 produced similar effects, which also were dependent on the presence of PPAR-α. Subchronic treatment with OEA reduced body weight gain and triacylglycerol content in liver and adipose tissue of diet-induced obese rats and wild-type mice, but not in obese PPAR-α–/– mice. The results suggest that OEA stimulates fat utilization through activation of PPAR-α and that this effect may contribute to its anti-obesity actions. Amides of long-chain fatty acids with ethanolamine (FAE) 1The abbreviations used are: FAE, fatty acid with ethanolamine; OEA, oleoylethanolamide; PPAR, peroxisome proliferator-activated receptor; FAT/CD36, fatty acid translocase; UCP-2, uncoupling protein-2; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. are a family of lipid mediators produced through the concerted action of two enzymes present in mammalian cells: N-acyltransferase, which transfers a fatty acid from the sn-1 position of a donor phospholipid to the free amine in phosphatidylethanolamine, producing N-acyl-phosphatidylethanolamine; and phospholipase D, which converts N-acyl-phosphatidylethanolamine to FAE (1Schmid H.H. Schmid P.C. Natarajan V. Chem. Phys. Lipids. 1996; 80: 133-142Crossref PubMed Scopus (157) Google Scholar, 2Sun Y.X. Tsuboi K. Okamoto Y. Tonai T. Murakami M. Kudo I. Ueda N. Biochem. J. 2004; (in press)Google Scholar). The FAE are hydrolyzed intracellularly to fatty acids and ethanolamine by the action of fatty acid amide hydrolase enzymes (3Schmid P.C. Zuzarte-Augustin M.L. Schmid H.H. J. Biol. Chem. 1985; 260: 14145-14149Abstract Full Text PDF PubMed Google Scholar, 4Cravatt B.F. Giang D.K. Mayfield S.P. Boger D.L. Lerner R.A. Gilula N.B. Nature. 1996; 384: 83-87Crossref PubMed Scopus (1795) Google Scholar, 5Ueda H. Hamabe W. Nippon Yakurigaku Zasshi. 2002; 119: 79-88Crossref PubMed Scopus (1) Google Scholar). Although the FAE were first described four decades ago (6Colodzin M. Bachur N. Weissbach H. Udenfriend S. Biochem. Biophys. Res. Commun. 1963; 10: 165-170Crossref PubMed Scopus (23) Google Scholar), they did not attract much attention until the discovery that a polyunsaturated member of this family, anandamide (arachidonoylethanolamide), is an endogenous ligand for cannabinoid receptors, G protein-coupled receptors targeted by the marijuana constituent Δ9-tetrahydrocannabinol (7Devane W.A. Hanus L. Breuer A. Pertwee R.G. Stevenson L.A. Griffin G. Gibson D. Mandelbaum A. Etinger A. Mechoulam R. Science. 1992; 258: 1946-1949Crossref PubMed Scopus (4685) Google Scholar). Anandamide is now established as a brain endocannabinoid messenger (8Piomelli D. Nat. Rev. Neurosci. 2003; 4: 873-884Crossref PubMed Scopus (1614) Google Scholar) and multiple roles for other FAE have also been proposed (9Mazzari S. Canella R. Petrelli L. Marcolongo G. Leon A. Eur. J. Pharmacol. 1996; 300: 227-236Crossref PubMed Scopus (309) Google Scholar, 10Calignano A. La Rana G. Giuffrida A. Piomelli D. Nature. 1998; 394: 277-281Crossref PubMed Scopus (951) Google Scholar, 11Rodríguez de Fonseca F. Navarro M. Gómez R. Escuredo L. Nava F. Fu J. Murillo-Rodríguez E. Giuffrida A. LoVerme J. Gaetani S. Kathuria S. Gall C. Piomelli D. Nature. 2001; 414: 209-212Crossref PubMed Scopus (596) Google Scholar). One emerging function of these lipid mediators is the regulation of feeding behavior. Anandamide causes overeating in rats because of its ability to activate cannabinoid receptors (12Berry E.M. Mechoulam R. Pharmacol. Ther. 2002; 95: 185-190Crossref PubMed Scopus (157) Google Scholar). This action is of therapeutic relevance: cannabinoid agonists such as Δ9-tetrahydrocannabinol are currently used to alleviate anorexia and nausea in AIDS patients, whereas the CB1 antagonist rimonabant (SR141716A) was recently found to be effective in late-stage clinical trials for the treatment of obesity (12Berry E.M. Mechoulam R. Pharmacol. Ther. 2002; 95: 185-190Crossref PubMed Scopus (157) Google Scholar). In contrast to anandamide, the monounsaturated FAE oleoylethanolamide (OEA) decreases food intake and body weight gain through a cannabinoid receptor-independent mechanism (11Rodríguez de Fonseca F. Navarro M. Gómez R. Escuredo L. Nava F. Fu J. Murillo-Rodríguez E. Giuffrida A. LoVerme J. Gaetani S. Kathuria S. Gall C. Piomelli D. Nature. 2001; 414: 209-212Crossref PubMed Scopus (596) Google Scholar, 13Gaetani S. Oveisi F. Piomelli D. Neuropsychopharmacology. 2003; 28: 1311-1316Crossref PubMed Scopus (132) Google Scholar). Pharmacological and molecular biological experiments have demonstrated that these effects result from the high affinity binding of OEA to, and consequent activation of, the nuclear receptor PPAR-α (peroxisome proliferator-activated receptor α) (14Fu J. Gaetani S. Oveisi F. Lo Verme J. Serrano A. Rodriguez de Fonseca F. Rosengarth A. Luecke H. Di Giacomo B. Tarzia G. Piomelli D. Nature. 2003; 425: 90-93Crossref PubMed Scopus (895) Google Scholar). Because PPAR-α serves an essential function in the regulation of lipid metabolism (15Berger J. Moller D.E. Annu. Rev. Med. 2002; 53: 409-435Crossref PubMed Scopus (2096) Google Scholar, 16Bocher V. Chinetti G. Fruchart J.C. Staels B. J. Soc. Biol. 2002; 196: 47-52Crossref PubMed Scopus (43) Google Scholar) we investigated whether OEA may also influence nutrient utilization by altering fat storage and catabolism. Chemicals—FAE synthesis was conducted as described (17Giuffrida A. Rodríguez de Fonseca F. Piomelli D. Anal. Biochem. 2000; 280: 87-93Crossref PubMed Scopus (150) Google Scholar). For in vitro experiments, drugs were dissolved in dimethyl sulfoxide and used at a final dimethyl sulfoxide concentration of 0.1–0.2 (v/v). For in vivo experiments, drugs were dissolved in a vehicle of 70% dimethyl sulfoxide/sterile saline (acute administrations) or 90% sterile saline, 5% polyethylene glycol, 5% Tween 80 (subchronic administrations). Cell and Tissue Preparation—Hepatocytes (18Beynen A.C. Vaartjes W.J. Geelen M.J. Diabetes. 1979; 28: 828-835Crossref PubMed Scopus (95) Google Scholar) and epididymal adipocytes (19Rodbell M. J. Biol. Chem. 1964; 239: 375-380Abstract Full Text PDF PubMed Google Scholar) were isolated by collagenase digestion of freshly isolated tissue from free-feeding male Wistar rats (150–200 g, Charles River, Wilmington, MA) or PPAR-α–/– mice (C57.129S4-Ppara(tm1Gonz); Taconic M&B, Ry, Denmark) and their corresponding wild-type C57BL/6N controls. Heart myocytes were prepared by collagenase digestion of embryonic rat hearts and maintained in primary culture as described (20Flink I.L. Edwards J.G. Bahl J.J. Liew C.C. Sole M. Morkin E. J. Biol. Chem. 1992; 267: 9917-9924Abstract Full Text PDF PubMed Google Scholar). Rat plasma was prepared by centrifugation of EDTA-treated (0.02 m) blood obtained by cardiac puncture. Lipolysis—Glycerol was determined spectrophotometrically in cell incubation media or plasma using a commercial kit (Sigma). Fatty acid release was measured in cells labeled by incubation with [3H]oleic acid (2 μCi per well, Amersham Biosciences) for 1 h at 37°C. After labeling, the cells were washed with ice-cold Krebs-Ringer buffer supplemented with 20 mm Hepes, 2 mm glucose, and 2% fatty acid-free bovine serum albumin (pH 7.4) and incubated for 30 min at 37 °C in 1 ml of buffer; the incubation medium was separated by centrifugation and fatty acids were isolated by solvent extraction followed by thin-layer chromatography (21Blázquez C. Galve-Roperh I. Guzmán M. FASEB J. 2000; 14: 2315-2322Crossref PubMed Scopus (141) Google Scholar). Plasma fatty acids were measured with a commercial kit (Wako Chemicals, Richmond, VA). Fatty Acid Oxidation—Fatty acid oxidation was measured using [1-14C]oleic acid as a substrate (0.4 mm, 0.5 μCi per sample; American Radiolabeled Chemicals, St. Louis, MO). In soleus muscle strips and heart myocytes, fatty acid oxidation to CO2 was determined by trapping released [14C]CO2 as bicarbonate in wells containing filter paper soaked with benzethonium hydroxide (1 m in methanol) (22Blázquez C. Sánchez C. Velasco G. Guzmán M. J. Neurochem. 1998; 71: 1597-1606Crossref PubMed Scopus (79) Google Scholar). In hepatocytes, [14C]ketone bodies, which constitute about 90% of total fatty acid oxidation products, were determined as non-volatile acid-soluble products (23Guzmán M. Geelen M.J. Biochem. J. 1992; 287: 487-492Crossref PubMed Scopus (40) Google Scholar). Glucose Uptake and Oxidation—Glucose uptake was measured by using 2-d-[3H]deoxyglucose as a substrate (1 μCi per sample, Amersham Biosciences). Cells in suspension (adipocytes or hepatocytes) were rapidly separated from the incubation medium by centrifugation, whereas in the case of attached heart myocytes and soleus muscle strips the medium was removed by aspiration. Samples were washed with ice-cold buffer, and radioactivity was counted in perchloric acid extracts. Glucose oxidation was measured by using d-[U-14C]glucose as a substrate (1 μCi per sample; Amersham Biosciences), trapping [14C]CO2 on filter paper, as described above. Tissue Lipids and Protein—Tissue triacylglycerols were extracted with chloroform:methanol:NaCl (1 m) (1:1:0.5), suspended in a solvent of tert-butanol:methanol:Triton X-114 (3:1:1), and measured using a commercial kit (GPO-Trinder; Sigma). Tissue protein content was determined using a commercial kit (Bio-Rad). Polymerase Chain Reaction—Reverse transcription of 2 μg of total RNA was carried out with 0.2 μg of oligo(dT)12–18 primer for 50 min at 42 °C, and real time quantitative polymerase chain reaction was done with an ABI PRISM 7700 sequence detection system (Applied Biosystems, Foster City, CA). Primer/probe sets were designed using Primer Express software (Applied Biosystems) and gene sequences from and were at The sequences for the rat were as For and For fat fatty and For fat fatty acid and For uncoupling and For glyceraldehyde-3-phosphate and RNA were by as an and were as described V. M.J. Anal. Biochem. 2000; PubMed Scopus Google Scholar). male Wistar rats or male PPAR-α–/– and wild-type mice were a was weight or After or the for 2 or of vehicle or OEA (5 mg 30 min The of rats vehicle intake and body weight were measured the of the experiments, the were for h to blood and tissue were used to plasma glucose and as as and St. MO). are as of The of was using or of followed by a multiple or a as OEA in of freshly dissociated rat adipocytes in the presence of OEA 30 the release of fatty acids and glycerol the medium OEA had no effect on glucose uptake or of whether the cells were isolated from free-feeding or rats not OEA did not glucose uptake OEA The effects of OEA were concentration-dependent effective and structurally as acid and anandamide had no such effect Because lipolysis is through protein J. Biol. Chem. Full Text PDF PubMed Google Scholar), we examined whether this messenger in the effects of a concentration that produced lipolysis OEA did not or (in OEA, 0.5 OEA 0.5 OEA the (5 μm) had no effect on or lipolysis not The results suggest that OEA lipolysis in isolated rat adipocytes through a mechanism that is of or OEA in of OEA to rats (5 mg kg–1, produced a in the of fatty acids and which was followed by a in the concentration of a of fatty acid oxidation This was effective mg and by a in the triacylglycerol content of epididymal fat and but not skeletal muscle plasma glucose OEA as did of and in OEA, 30 OEA, in OEA, 30 OEA, acid and anandamide had no effect in vivo at of the to 20 mg kg–1, PPAR-α in of OEA (5 mg kg–1, to mice reduced liver triacylglycerol content 1 h the of PPAR-α in this we used we examined the effects of the synthetic PPAR-α agonist which is structurally to OEA J. Med. Chem. 2000; PubMed Scopus Google Scholar). a that PPAR-α in vivo mg kg–1, (14Fu J. Gaetani S. Oveisi F. Lo Verme J. Serrano A. Rodriguez de Fonseca F. Rosengarth A. Luecke H. Di Giacomo B. Tarzia G. Piomelli D. Nature. 2003; 425: 90-93Crossref PubMed Scopus (895) Google Scholar), Wy-14643 reduced liver triacylglycerol to the same as did mg OEA we examined whether of PPAR-α the to OEA and Wy-14643 in In contrast with their effects in wild-type mice, both drugs liver triacylglycerol in mice in which PPAR-α had been deleted by homologous recombination T. J. D.L. H. Biol. PubMed Scopus Google Scholar) did not the for this an is in the of OEA activate other nuclear receptors S. 2001; PubMed Scopus Google Scholar). we investigated whether of PPAR-α the to OEA or Wy-14643 in of adipocytes isolated from wild-type mice with stimulated lipolysis whereas no such effect was in adipocytes isolated from PPAR-α–/– mice the of PPAR-α in the to OEA, we wild-type and PPAR-α–/– mice for with a and for with OEA (5 mg kg–1, a that was to body weight gain (14Fu J. Gaetani S. Oveisi F. Lo Verme J. Serrano A. Rodriguez de Fonseca F. Rosengarth A. Luecke H. Di Giacomo B. Tarzia G. Piomelli D. Nature. 2003; 425: 90-93Crossref PubMed Scopus (895) Google Scholar). In wild-type mice, this treatment a in liver and fat triacylglycerol content and but had no such effect in PPAR-α–/– mice and the mechanism by which these we the effects of OEA on the of in lipid In h a of OEA mg we found of PPAR-α in adipose tissue and skeletal muscle two the regulation of fatty and fatty acid which for that participate in the of fatty acids W. L. A. T. Lipids. 2001; PubMed Scopus Google Scholar), were by OEA treatment in and and muscle tissue G and were by an in the of and which is to a in energy utilization T. N. M. S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. FASEB J. 1998; PubMed Scopus Google Scholar). OEA Fatty Acid in a in the of fatty acid that OEA may also this In of this we found that of rat soleus muscle strips with OEA enhanced fatty acid oxidation in a concentration-dependent 2 μm) and whereas no effect on glucose uptake or oxidation the of PPAR-α in this we examined the effect of OEA on soleus muscle strips isolated from PPAR-α–/– mice and wild-type controls. OEA stimulated fatty acid oxidation in tissue from wild-type but not PPAR-α–/– mice is the case with acid and anandamide had no effect on fatty acid oxidation The ability of OEA to enhance fatty acid oxidation was not to skeletal as similar results were obtained in primary of rat heart myocytes and in dissociated rat Although a in was with that produced by 20 a 5% of in the of of OEA to obese rats or mice food intake and body weight gain (11Rodríguez de Fonseca F. Navarro M. Gómez R. Escuredo L. Nava F. Fu J. Murillo-Rodríguez E. Giuffrida A. LoVerme J. Gaetani S. Kathuria S. Gall C. Piomelli D. Nature. 2001; 414: 209-212Crossref PubMed Scopus (596) Google Scholar, J. Gaetani S. Oveisi F. Lo Verme J. Serrano A. Rodriguez de Fonseca F. Rosengarth A. Luecke H. Di Giacomo B. Tarzia G. Piomelli D. Nature. 2003; 425: 90-93Crossref PubMed Scopus (895) Google Scholar), whether the effects of this may be to its this we first obesity in rats by feeding with a for and with OEA (5 mg kg–1, or vehicle for 2 In with results (11Rodríguez de Fonseca F. Navarro M. Gómez R. Escuredo L. Nava F. Fu J. Murillo-Rodríguez E. Giuffrida A. LoVerme J. Gaetani S. Kathuria S. Gall C. Piomelli D. Nature. 2001; 414: 209-212Crossref PubMed Scopus (596) Google Scholar, J. Gaetani S. Oveisi F. Lo Verme J. Serrano A. Rodriguez de Fonseca F. Rosengarth A. Luecke H. Di Giacomo B. Tarzia G. Piomelli D. Nature. 2003; 425: 90-93Crossref PubMed Scopus (895) Google Scholar), we found that OEA produced a of body weight gain which was by a but in the of food the treatment The also reduced fat and triacylglycerol content in both fat and liver that the in food intake by OEA treatment for the in body weight gain and fat this we in the a of which the same of food by with vehicle rats as much weight as did free-feeding in these fat and triacylglycerol content in adipose tissue and liver were to of free-feeding controls. whereas OEA reduces body weight gain in rats by food intake (11Rodríguez de Fonseca F. Navarro M. Gómez R. Escuredo L. Nava F. Fu J. Murillo-Rodríguez E. Giuffrida A. LoVerme J. Gaetani S. Kathuria S. Gall C. Piomelli D. Nature. 2001; 414: 209-212Crossref PubMed Scopus (596) Google Scholar), the of this in obese a to its ability to stimulate fatty acid utilization. The of this is that OEA stimulates lipolysis and fatty acid oxidation through activation of the nuclear receptor PPAR-α. The effects of OEA were both in vitro and in and the of PPAR-α in such effects was by two OEA was at lipolysis and fatty acid oxidation in wild-type mice, but not in mice in the synthetic PPAR-α agonist Wy-14643 similar effects, which were also on PPAR-α results are with the proposed of OEA as a high affinity agonist for PPAR-α (14Fu J. Gaetani S. Oveisi F. Lo Verme J. Serrano A. Rodriguez de Fonseca F. Rosengarth A. Luecke H. Di Giacomo B. Tarzia G. Piomelli D. Nature. 2003; 425: 90-93Crossref PubMed Scopus (895) Google Scholar) and a of this lipid in two of energy feeding (11Rodríguez de Fonseca F. Navarro M. Gómez R. Escuredo L. Nava F. Fu J. Murillo-Rodríguez E. Giuffrida A. LoVerme J. Gaetani S. Kathuria S. Gall C. Piomelli D. Nature. 2001; 414: 209-212Crossref PubMed Scopus (596) Google Scholar, J. Gaetani S. Oveisi F. Lo Verme J. Serrano A. Rodriguez de Fonseca F. Rosengarth A. Luecke H. Di Giacomo B. Tarzia G. Piomelli D. Nature. 2003; 425: 90-93Crossref PubMed Scopus (895) Google Scholar) and fat utilization have (11Rodríguez de Fonseca F. Navarro M. Gómez R. Escuredo L. Nava F. Fu J. Murillo-Rodríguez E. Giuffrida A. LoVerme J. Gaetani S. Kathuria S. Gall C. Piomelli D. Nature. 2001; 414: 209-212Crossref PubMed Scopus (596) Google Scholar, J. Gaetani S. Oveisi F. Lo Verme J. Serrano A. Rodriguez de Fonseca F. Rosengarth A. Luecke H. Di Giacomo B. Tarzia G. Piomelli D. Nature. 2003; 425: 90-93Crossref PubMed Scopus (895) Google Scholar) that OEA, by activating reduces body weight gain in The present the of whether fat utilization to these effects (14Fu J. Gaetani S. Oveisi F. Lo Verme J. Serrano A. Rodriguez de Fonseca F. Rosengarth A. Luecke H. Di Giacomo B. Tarzia G. Piomelli D. Nature. 2003; 425: 90-93Crossref PubMed Scopus (895) Google Scholar). The to this to on the experiments that of may for the of OEA in rats (11Rodríguez de Fonseca F. Navarro M. Gómez R. Escuredo L. Nava F. Fu J. Murillo-Rodríguez E. Giuffrida A. LoVerme J. Gaetani S. Kathuria S. Gall C. Piomelli D. Nature. 2001; 414: 209-212Crossref PubMed Scopus (596) Google Scholar), but not in rats obese by a in the in lipid metabolism a This is by the ability demonstrated by OEA to tissue triacylglycerol The effects of this lipid on fatty acid oxidation may also be in this as OEA is to the of that participate in fatty acid utilization and energy by results to the molecular mechanism the of Although PPAR-α activation of lipid and enzymes (15Berger J. Moller D.E. Annu. Rev. Med. 2002; 53: 409-435Crossref PubMed Scopus (2096) Google Scholar, 16Bocher V. Chinetti G. Fruchart J.C. Staels B. J. Soc. Biol. 2002; 196: 47-52Crossref PubMed Scopus (43) Google Scholar), the time of lipolysis that may be by and the activation of have been to contribute in to the action of receptors T. A. K. Nature. 2000; PubMed Scopus Google Scholar), but they have not been for PPAR-α or other of the these may not to the mechanism by which OEA but also on the ability of the to (11Rodríguez de Fonseca F. Navarro M. Gómez R. Escuredo L. Nava F. Fu J. Murillo-Rodríguez E. Giuffrida A. LoVerme J. Gaetani S. Kathuria S. Gall C. Piomelli D. Nature. 2001; 414: 209-212Crossref PubMed Scopus (596) Google Scholar, 13Gaetani S. Oveisi F. Piomelli D. Neuropsychopharmacology. 2003; 28: 1311-1316Crossref PubMed Scopus (132) Google Scholar). The of the of OEA is the high of OEA found in fat mice, suggest that this may a in this to of such as Annu. Rev. 2003; PubMed Scopus Google Scholar) and 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). the of of fatty acid oxidation in skeletal the tissue for the of body fatty acid is with that by R.A. Diabetes. PubMed Google Scholar) and J. S. D. S. A. 2001; PubMed Scopus Google Scholar). the suggest that OEA may not have a on glucose PPAR-α agonists such as the are currently used in the as and the of these at PPAR-α are that of OEA (14Fu J. Gaetani S. Oveisi F. Lo Verme J. Serrano A. Rodriguez de Fonseca F. Rosengarth A. Luecke H. Di Giacomo B. Tarzia G. Piomelli D. Nature. 2003; 425: 90-93Crossref PubMed Scopus (895) Google Scholar) they not food intake (14Fu J. Gaetani S. Oveisi F. Lo Verme J. Serrano A. Rodriguez de Fonseca F. Rosengarth A. Luecke H. Di Giacomo B. Tarzia G. Piomelli D. Nature. 2003; 425: 90-93Crossref PubMed Scopus (895) Google Scholar, J. Res. 2001; Full Text Full Text PDF PubMed Google Scholar). The of OEA that this lipid may a for the of anti-obesity drugs with and Gaetani and Kathuria for and with