Oleoylethanolamide, an endogenous PPAR-alpha agonist, lowers body weight and hyperlipidemia in obese rats.
The fatty-acid ethanolamide, oleoylethanolamide (OEA), is a naturally occurring lipid that regulates feeding and body weight [Rodriguez de Fonseca, F., Navarro, M., Gomez, R., Escuredo, L., Nava, F., Fu, J., Murillo-Rodriguez, E., Giuffrida, A., LoVerme, J., Gaetani, S., Kathuria, S., Gall, C., Piomelli, D., 2001. An anorexic lipid mediator regulated by feeding. Nature 414, 209-212], and serves as an endogenous agonist of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) [Fu, 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., 2003. Oleoylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 425, 90-93], a ligand-activated transcription factor that regulates several aspects of lipid metabolism [. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr. Rev. 20, 649-688]). OEA reduces food intake in wild-type mice, but not in mice deficient in PPAR-alpha (PPAR-alpha(-/-)), an effect that is also observed with the PPAR-alpha agonists Wy-14643 and GW7647 [Brown, P.J., Chapman, J.M., Oplinger, J.A., Stuart, L.W., Willson, T.M. and Wu, Z., 2000. Chemical compounds as selective activators of PPAR-alpha. PCT Int. Appl., 32; . The PPARs: from orphan receptors to drug discovery. J. Med. Chem. 43, 527-550]. By contrast, specific agonists of PPAR-delta/beta (GW501516) or PPAR-gamma (ciglitazone) have no such effect. In obese Zucker rats, which lack functional leptin receptors, OEA reduces food intake and lowers body-weight gain along with plasma lipid levels. Similar effects are seen in diet-induced obese rats and mice. In the present study, we report that subchronic OEA treatment (5mgkg(-1), intraperitoneally, i.p., once daily for two weeks) in Zucker rats initiates transcription of PPAR-alpha and other PPAR-alpha target genes, including fatty-acid translocase (FAT/CD36), liver fatty-acid binding protein (L-FABP), and uncoupling protein-2 (UCP-2). Moreover, OEA decreases neutral lipid content in hepatocytes, as assessed by Oil red O staining, as well as serum cholesterol and triglyceride levels. The results suggest that OEA regulates lipid metabolism and that this effect may contribute to its anti-obesity properties.
Fu
Jin
J
Department of Psychiatry, University of California, Irvine, CA 92697-4625, USA. jinf@uci.edu
Oveisi
Fariba
F
Gaetani
Silvana
S
Lin
Edward
E
Piomelli
Daniele
D
D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology; D018955:CD36 Antigens / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D003066:Coenzyme A Ligases / Q000235:genetics; D004435:Eating / Q000187:drug effects*; D063388:Endocannabinoids; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006949:Hyperlipidemias / Q000188:drug therapy*; D007473:Ion Channels / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics; D009765:Obesity / Q000188:drug therapy*; D009829:Oleic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics; D010671:Phenylurea Compounds / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011920:Rats, Inbred WF; D011924:Rats, Zucker; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood; D000071246:Uncoupling Protein 2
D002087:Butyrates; D018955:CD36 Antigens; D063388:Endocannabinoids; C493321:Fabp1 protein, rat; D050556:Fatty Acid-Binding Proteins; C425931:GW 501516; C453899:GW 7647; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009829:Oleic Acids; D047493:PPAR alpha; D010671:Phenylurea Compounds; D011743:Pyrimidines; D012333:RNA, Messenger; D013844:Thiazoles; D045162:Thiazolidinediones; D014280:Triglycerides; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; C488250:oleoylethanolamide; C006253:pirinixic acid; D002784:Cholesterol; D003066:Coenzyme A Ligases; C039671:ciglitazone