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[This retracts the article DOI: 10.1155/2008/961753.].

[This retracts the article DOI: 10.1155/2016/9282087.].

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 (Applied and from and were at The 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

Long-chain fatty acids (FA) coordinately induce the expression of a panel of genes involved in cellular FA metabolism in cardiac muscle cells, thereby promoting their own metabolism. These effects are likely to be mediated by peroxisome proliferator-activated receptors (PPARs). Whereas the significance of PPARalpha in FA-mediated expression has been demonstrated, the role of the PPARbeta/delta and PPARgamma isoforms in cardiac lipid metabolism is unknown. To explore the involvement of each of the PPAR isoforms, neonatal rat cardiomyocytes were exposed to FA or to ligands specific for either PPARalpha (Wy-14,643), PPARbeta/delta (L-165041, GW501516), or PPARgamma (ciglitazone and rosiglitazone). Their effect on FA oxidation rate, expression of metabolic genes, and muscle-type carnitine palmitoyltransferase-1 (MCPT-1) promoter activity was determined. Consistent with the PPAR isoform expression pattern, the FA oxidation rate increased in cardiomyocytes exposed to PPARalpha and PPARbeta/delta ligands, but not to PPARgamma ligands. Likewise, the FA-mediated expression of FA-handling proteins was mimicked by PPARalpha and PPARbeta/delta, but not by PPARgamma ligands. As expected, in embryonic rat heart-derived H9c2 cells, which only express PPARbeta/delta, the FA-induced expression of genes was mimicked by the PPARbeta/delta ligand only, indicating that FA also act as ligands for the PPARbeta/delta isoform. In cardiomyocytes, MCPT-1 promoter activity was unresponsive to PPARgamma ligands. However, addition of PPARalpha and PPARbeta/delta ligands dose-dependently induced promoter activity. Collectively, the present findings demonstrate that, next to PPARalpha, PPARbeta/delta, but not PPARgamma, plays a prominent role in the regulation of cardiac lipid metabolism, thereby warranting further research into the role of PPARbeta/delta in cardiac disease.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that play an important role in the regulation of genes involved in lipid utilization and storage, lipoprotein metabolism, adipocyte differentiation, and insulin action. The three isoforms of the PPAR family, i.e. alpha, delta, and gamma, have distinct tissue distribution patterns. PPAR-alpha is predominantly present in the liver, and PPAR-gamma in adipose tissue, whereas PPAR-delta is ubiquitously expressed. A recent study reported increased PPAR-gamma messenger RNA (mRNA) expression in the liver in ob/ob mice; however, it is not known whether increased PPAR-gamma expression in the liver has any functional consequences. The expression of PPAR-alpha and -delta in the liver in obesity has not been determined. We have now examined the mRNA levels of PPAR-alpha, -delta, and -gamma in three murine models of obesity, namely, ob/ob (leptin-deficient), db/db (leptin-receptor deficient), and serotonin 5-HT2c receptor (5-HT2cR) mutant mice. 5-HT2cR mutant mice develop a late-onset obesity that is associated with higher plasma leptin levels. Our results show that PPAR-alpha mRNA levels in the liver are increased by 2- to 3-fold in all three obese models, whereas hepatic PPAR-gamma mRNA levels are increased by 7- to 9-fold in ob/ob and db/db mice and by 2-fold in obese 5-HT2cR mutant mice. PPAR-delta mRNA expression is not altered in ob/ob or db/db mice. To determine whether increased PPAR-gamma expression in the liver has any functional consequences, we examined the effect of troglitazone treatment on the hepatic mRNA levels of several PPAR-gamma-responsive adipose tissue-specific genes that have either no detectable or very low basal expression in the liver. The treatment of lean control mice with troglitazone significantly increased the expression of adipocyte fatty acid-binding protein (aP2) and fatty acid translocase (FAT/CD36) in the liver. This troglitazone-induced increase in the expression of aP2 and FAT/CD36 was markedly enhanced in the liver in ob/ob mice. Troglitazone also induced a pronounced increase in the expression of uncoupling protein-2 in the liver in ob/ob mice. In contrast to the liver, troglitazone did not increase the expression of aP2, FAT/CD36, and uncoupling protein-2 in adipose tissue in lean or ob/ob mice. Taken together, our results suggest that the effects of PPAR-gamma activators on lipid metabolism and energy homeostasis in obesity and type 2 diabetes may be partly mediated through their effects on PPAR-gamma in the liver.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear hormone receptor expressed predominantly in adipose tissue, where it plays a central role in the control of adipocyte gene expression and differentiation. Because there are two additional PPAR isoforms, PPARalpha and PPARdelta, and these are also expressed at some level in certain adipose depots, we have compared directly the adipogenic potential of all three receptors. Ectopically expressed PPARgamma powerfully induces adipogenesis at a morphological and molecular level in response to a number of PPARgamma activators. PPARalpha is less adipogenic but is able to induce significant differentiation in response to strong PPARalpha activators. Expression and activation of PPARdelta did not stimulate adipogenesis. Of the three PPARs, only PPARgamma can cooperate with C/EBPalpha in the promotion of adipogenesis. To begin to investigate the functional basis for the differential adipogenic activity of the PPAR isoforms, we have examined their ability to bind to several PPAR DNA response sequences. Compared with PPARalpha and PPARdelta, PPARgamma shows preferential binding to two well-characterized regulatory sequences derived from a fat-specific gene, ARE6 and ARE7. These data strongly suggest that PPARgamma is the predominant receptor regulating adipogenesis; however, they also suggest that PPARalpha may play a role in differentiation of certain adipose depots in response to a different set of physiologic activators or in certain disease states.

The orphan nuclear receptor, peroxisome proliferator-activated receptor (PPAR) gamma, is implicated in mediating expression of fat-specific genes and in activating the program of adipocyte differentiation. The potential for regulation of PPAR gamma gene expression in vivo is unknown. We cloned a partial mouse PPAR gamma cDNA and developed an RNase protection assay that permits simultaneous quantitation of mRNAs for both gamma l and gamma 2 isoforms encoded by the PPAR gamma gene. Probes for detection of adipocyte P2, the obese gene product, leptin, and 18S mRNAs were also employed. Both gamma l and gamma 2 mRNAs were abundantly expressed in adipose tissue. PPAR gamma 1 expression was also detected at lower levels in liver, spleen, and heart; whereas, gamma l and gamma 2 mRNA were expressed at low levels in skeletal muscle. Adipose tissue levels of gamma l and gamma 2 were not altered in two murine models of obesity (gold thioglucose and ob/ob), but were modestly increased in mice with toxigene-induced brown fat ablation uncoupling protein diphtheria toxin A mice. Fasting (12-48 h) was associated with an 80% fall in PPAR gamma 2 and a 50% fall in PPAR gamma mRNA levels in adipose tissue. Western blot analysis demonstrated a marked effect of fasting to reduce PPAR gamma protein levels in adipose tissue. Similar effects of fasting on PPAR gamma mRNAs were noted in all three models of obesity. Insulin-deficient (streptozotocin) diabetes suppressed adipose tissue gamma l and gamma 2 expression by 75% in normal mice with partial restoration during insulin treatment. Levels of adipose tissue PPAR gamma 2 mRNA were increased by 50% in normal mice exposed to a high fat diet. In obese uncoupling protein diphtheria toxin A mice, high fat feeding resulted in de novo induction of PPAR gamma 2 expression in liver. We conclude (a) PPAR gamma 2 mRNA expression is most abundant in adipocytes in normal mice, but lower level expression is seen in skeletal muscle; (b) expression of adipose tissue gamma1 or gamma2 mRNAs is increased in only one of the three models of obesity; (c) PPAR gamma 1 and gamma 2 expression is downregulated by fasting and insulin-deficient diabetes; and (d) exposure of mice to a high fat diet increases adipose tissue expression of PPAR gamma (in normal mice) and induces PPAR gamma 2 mRNA expression in liver (in obese mice). These findings demonstrate in vivo modulation of PPAR gamma mRNA levels over a fourfold range and provide an additional level of regulation for the control of adipocyte development and function.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone-receptor superfamily. Originally cloned in 1990, PPARs were found to be mediators of pharmacologic agents that induce hepatocyte peroxisome proliferation. PPARs also are expressed in cells of the cardiovascular system. PPAR gamma appears to be highly expressed during atherosclerotic lesion formation, suggesting that increased PPAR gamma expression may be a vascular compensatory response. Also, ligand-activated PPAR gamma decreases the inflammatory response in cardiovascular cells, particularly in endothelial cells. PPAR alpha, similar to PPAR gamma, also has pleiotropic effects in the cardiovascular system, including antiinflammatory and antiatherosclerotic properties. PPAR alpha activation inhibits vascular smooth muscle proinflammatory responses, attenuating the development of atherosclerosis. However, PPAR delta overexpression may lead to elevated macrophage inflammation and atherosclerosis. Conversely, PPAR delta ligands are shown to attenuate the pathogenesis of atherosclerosis by improving endothelial cell proliferation and survival while decreasing endothelial cell inflammation and vascular smooth muscle cell proliferation. Furthermore, the administration of PPAR ligands in the form of TZDs and fibrates has been disappointing in terms of markedly reducing cardiovascular events in the clinical setting. Therefore, a better understanding of PPAR-dependent and -independent signaling will provide the foundation for future research on the role of PPARs in human cardiovascular biology.

The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPAR gamma, PPAR alpha, and PPAR delta, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand-activated transcription factors. They exist in three isoforms: PPARα, PPARβ/δ, and PPARγ. For all PPARs, lipids are endogenous ligands, linking them directly to metabolism. PPARs form heterodimers with retinoic X receptors, and upon ligand binding, they modulate the gene expression of downstream target genes, depending on the presence of co-repressors or co-activators. This results in a complex, cell type-specific regulation of proliferation, differentiation, and cell survival. PPARs are linked to metabolic disorders and are interesting pharmaceutical targets. PPARα and PPARγ agonists are already in clinical use for the treatment of hyperlipidemia and type 2 diabetes, respectively. More recently, PPARβ/δ activation came into focus as an interesting novel approach for the treatment of metabolic syndrome and associated cardiovascular diseases; however, this has been limited due to the highly controversial function of PPARβ/δ in cancer. This Special Issue of Cells brings together the most recent advances in understanding the various aspects of the action of PPARs, and it provides new insights into our understanding of PPARs, implying also the latest therapeutic perspectives for the utility of PPAR modulation in different disease settings.

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease phenotypes which start with simple steatosis and lipid accumulation in the hepatocytes - a typical histological lesions characteristic. It may progress to non-alcoholic steatohepatitis (NASH) that is characterized by hepatic inflammation and/or fibrosis and subsequent onset of NAFLD-related cirrhosis and hepatocellular carcinoma (HCC). Due to the central role of the liver in metabolism, NAFLD is regarded as a result of and contribution to the metabolic abnormalities seen in the metabolic syndrome. Peroxisome proliferator-activated receptors (PPARs) has three subtypes, which govern the expression of genes responsible for energy metabolism, cellular development, inflammation, and differentiation. The agonists of PPARα, such as fenofibrate and clofibrate, have been used as lipid-lowering drugs in clinical practice. Thiazolidinediones (TZDs) - ligands of PPARγ, such as rosiglitazone and pioglitazone, are also used in the treatment of type 2 diabetes (T2D) with insulin resistance (IR). Increasing evidence suggests that PPARβ/δ agonists have potential therapeutic effects in improving insulin sensitivity and lipid metabolism disorders. In addition, PPARs ligands have been considered as potential therapeutic drugs for hypertension, atherosclerosis (AS) or diabetic nephropathy. Their crucial biological roles dictate the significance of PPARs-targeting in medical research and drug discovery. Here, it reviews the biological activities, ligand selectivity and biological functions of the PPARs family, and discusses the relationship between PPARs and the pathogenesis of NAFLD and metabolic syndrome. This will open new possibilities for PPARs application in medicine, and provide a new idea for the treatment of fatty liver and related diseases.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner. Pemafibrate, due to its high selectivity, is likely to replace other PPARα agonists for dyslipidemia and cardiovascular diseases. PPARγ agonist pioglitazone showed tremendous promises in many non-metabolic disorders like chronic kidney disease, depression, inflammation, and autoimmune diseases. The clinical niche of PPARβ/δ agonists is less well-explored. Interestingly, dual- or pan-PPAR agonists, namely chiglitazar, saroglitazar, elafibranor, and lanifibranor, are gaining momentum with their optimistic outcomes in many diseases including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and primary biliary cholangitis. Notably, the preclinical and clinical development for PPAR antagonists remains unacceptably deficient. We anticipate the future design of better PPAR modulators with minimal off-target effects, high selectivity, superior bioavailability, and pharmacokinetics. This will open new possibilities for PPAR ligands in medicine.

The nuclear receptor family of PPARs was named for the ability of the original member to induce hepatic peroxisome proliferation in mice in response to xenobiotic stimuli. However, studies on the action and structure of the 3 human PPAR isotypes (PPARalpha, PPARdelta, and PPARgamma) suggest that these moieties are intimately involved in nutrient sensing and the regulation of carbohydrate and lipid metabolism. PPARalpha and PPARdelta appear primarily to stimulate oxidative lipid metabolism, while PPARgamma is principally involved in the cellular assimilation of lipids via anabolic pathways. Our understanding of the functions of PPARgamma in humans has been increased by the clinical use of potent agonists and by the discovery of both rare and severely deleterious dominant-negative mutations leading to a stereotyped syndrome of partial lipodystrophy and severe insulin resistance, as well as more common sequence variants with a much smaller impact on receptor function. These may nevertheless have much greater significance for the public health burden of metabolic disease. This Review will focus on the role of PPARgamma in human physiology, with specific reference to clinical pharmacological studies, and analysis of PPARG gene variants in the abnormal lipid and carbohydrate metabolism of the metabolic syndrome.

Pulmonary fibrosis is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in loss of alveolar function, destruction of normal lung architecture, and respiratory distress. Some types of fibrosis respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary fibrosis (IPF) have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary fibrosis, and there is variability in survival even among individuals with biopsy-proven IPF. Evidence is accumulating that the peroxisome proliferator-activated receptors (PPARs) play important roles in regulating processes related to fibrogenesis, including cellular differentiation, inflammation, and wound healing. PPARalpha agonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac fibrosis in animal models. In the mouse model of lung fibrosis induced by bleomycin, a PPARalpha agonist significantly inhibited the fibrotic response, while PPARalpha knockout mice developed more serious fibrosis. PPARbeta/delta appears to play a critical role in regulating the transition from inflammation to wound healing. PPARbeta/delta agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARgamma agonists. PPARgamma ligands oppose the profibrotic effect of TGF-beta, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. PPARgamma ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung fibrosis in vitro and in animal models. The clinical availability of potent and selective PPARalpha and PPARgamma agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.

Activation of T lymphocytes and their ensuing elaboration of proinflammatory cytokines, such as interferon (IFN)-gamma, represent a critical step in atherogenesis and arteriosclerosis. IFNgamma pathways also appear integral to the development of transplantation-associated arteriosclerosis (Tx-AA), limiting long-term cardiac allograft survival. Although disruption of these IFNgamma signaling pathways limits atherosclerosis and Tx-AA in animals, little is known about inhibitory regulation of proinflammatory cytokine production in humans. The present study investigated whether activators of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma, with their known antiinflammatory effects, might regulate the expression of proinflammatory cytokines in human CD4-positive T cells. Isolated human CD4-positive T cells express PPARalpha and PPARgamma mRNA and protein. Activation of CD4-positive T cells by anti-CD3 monoclonal antibodies significantly increased IFNgamma protein secretion from 0 to 504+/-168 pg/mL, as determined by ELISA. Pretreatment of cells with well-established PPARalpha (WY14643 or fenofibrate) or PPARgamma (BRL49653/rosiglitazone or pioglitazone) activators reduced anti-CD3-induced IFNgamma secretion in a concentration-dependent manner. PPAR activators also inhibited TNFalpha and interleukin-2 protein expression. In addition, PPAR activators markedly reduced cytokine mRNA expression in these cells. Such antiinflammatory actions were also evident in cell-cell interactions with medium conditioned by PPAR activator-treated T cells attenuating human monocyte CD64 expression and human endothelial cell major histocompatibility complex class II induction. Thus, activation of PPARalpha and PPARgamma in human CD4-positive T cells limits the expression of proinflammatory cytokines, such as IFNgamma, yielding potential therapeutic benefits in pathological processes, such as atherosclerosis and Tx-AA.

It has been more than 36 years since peroxisome proliferator-activated receptors (PPARs) were first recognized as enhancers of peroxisome proliferation. Consequently, many studies in different fields have illustrated that PPARs are nuclear receptors that participate in nutrient and energy metabolism and regulate cellular and whole-body energy homeostasis during lipid and carbohydrate metabolism, cell growth, cancer development, and so on. With increasing challenges to human health, PPARs have attracted much attention for their ability to ameliorate metabolic syndromes. In our previous studies, we found that the complex functions of PPARs may be used as future targets in obesity and atherosclerosis treatments. Here, we review three types of PPARs that play overlapping but distinct roles in nutrient and energy metabolism during different metabolic states and in different organs. Furthermore, research has emerged showing that PPARs also play many other roles in inflammation, central nervous system-related diseases, and cancer. Increasingly, drug development has been based on the use of several selective PPARs as modulators to diminish the adverse effects of the PPAR agonists previously used in clinical practice. In conclusion, the complex roles of PPARs in metabolic networks keep these factors in the forefront of research because it is hoped that they will have potential therapeutic effects in future applications.

Peroxisome proliferator-activated receptors (PPARs) are ligand binding transcription factors which function in many physiological roles including lipid metabolism, cell growth, differentiation, and apoptosis. PPARs and their ligands have been shown to play a role in cancer. In particular, PPARgamma ligands including endogenous prostaglandins and the synthetic thiazolidinediones (TZDs) can induce apoptosis of cancer cells with antitumor activity. Thus, PPARgamma ligands have a potential in both chemoprevention and therapy of several types of cancer either as single agents or in combination with other antitumor agents. Accordingly, the involvement of PPARgamma and its ligands in regulation of apoptosis of cancer cells have been extensively studied. Depending on cell types or ligands, induction of apoptosis in cancer cells by PPARgamma ligands can be either PPARgamma-dependent or -independent. Through increasing our understanding of the mechanisms of PPARgamma ligand-induced apoptosis, we can develop better strategies which may include combining other antitumor agents for PPARgamma-targeted cancer chemoprevention and therapy. This review will highlight recent research advances on PPARgamma and apoptosis in cancer.

Cannabinoids act at two classical cannabinoid receptors (CB1 and CB2), a 7TM orphan receptor and the transmitter-gated channel transient receptor potential vanilloid type-1 receptor. Recent evidence also points to cannabinoids acting at members of the nuclear receptor family, peroxisome proliferator-activated receptors (PPARs, with three subtypes alpha, beta (delta) and gamma), which regulate cell differentiation and lipid metabolism. Much evidence now suggests that endocannabinoids are natural activators of PPAR alpha. Oleoylethanolamide regulates feeding and body weight, stimulates fat utilization and has neuroprotective effects mediated through activation of PPAR alpha. Similarly, palmitoylethanolamide regulates feeding and lipid metabolism and has anti-inflammatory properties mediated by PPAR alpha. Other endocannabinoids that activate PPAR alpha include anandamide, virodhamine and noladin. Some (but not all) endocannabinoids also activate PPAR gamma; anandamide and 2-arachidonoylglycerol have anti-inflammatory properties mediated by PPAR gamma. Similarly, ajulemic acid, a structural analogue of a metabolite of Delta(9)-tetrahydrocannabinol (THC), causes anti-inflammatory effects in vivo through PPAR gamma. THC also activates PPAR gamma, leading to a time-dependent vasorelaxation in isolated arteries. Other cannabinoids which activate PPAR gamma include N-arachidonoyl-dopamine, HU210, WIN55212-2 and CP55940. In contrast, little research has been carried out on the effects of cannabinoids at PPAR delta. In this newly emerging area, a number of research questions remain unanswered; for example, why do cannabinoids activate some isoforms and not others? How much of the chronic effects of cannabinoids are through activation of nuclear receptors? And importantly, do cannabinoids confer the same neuro- and cardioprotective benefits as other PPAR alpha and PPAR gamma agonists? This review will summarize the published literature implicating cannabinoid-mediated PPAR effects and discuss the implications thereof.