Oleoylethanolamide, an endogenous PPAR-alpha agonist, lowers body weight and hyperlipidemia in obese rats.

Abstract

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.

• Authors: Jin Fu, Fariba Oveisi, Silvana Gaetani, Edward Lin, Daniele Piomelli
• Journal: Neuropharmacology (Neuropharmacology) Vol. 48 Issue 8 Pg. 1147-53 (Jun 2005) ISSN: 1873-7064 [Electronic] England
• PMID: 15910890 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Butyrates
• CD36 Antigens
• Endocannabinoids
• Fabp1 protein, rat
• Fatty Acid-Binding Proteins
• GW 501516
• GW 7647
• Ion Channels
• Mitochondrial Proteins
• Oleic Acids
• PPAR alpha
• Phenylurea Compounds
• Pyrimidines
• RNA, Messenger
• Thiazoles
• Thiazolidinediones
• Triglycerides
• Ucp2 protein, mouse
• Ucp2 protein, rat
• Uncoupling Protein 2
• oleoylethanolamide
• pirinixic acid
• Cholesterol
• Coenzyme A Ligases
• ciglitazone

Topics

• Animals
• Body Weight (drug effects)
• Butyrates (pharmacology)
• CD36 Antigens (genetics)
• Cholesterol (blood)
• Coenzyme A Ligases (genetics)
• Eating (drug effects)
• Endocannabinoids
• Fatty Acid-Binding Proteins (genetics)
• Hepatocytes (metabolism)
• Hyperlipidemias (drug therapy)
• Ion Channels (genetics)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondrial Proteins (genetics)
• Obesity (drug therapy)
• Oleic Acids (administration & dosage, pharmacology)
• PPAR alpha (agonists, genetics)
• Phenylurea Compounds (pharmacology)
• Pyrimidines (pharmacology)
• RNA, Messenger (metabolism)
• Rats
• Rats, Inbred WF
• Rats, Zucker
• Thiazoles (pharmacology)
• Thiazolidinediones (pharmacology)
• Triglycerides (blood)
• Uncoupling Protein 2