Oleylethanolamide (OEA) is a naturally occurring lipid that regulates satiety and body weight. Although structurally related to the endogenous cannabinoid anandamide, OEA does not bind to cannabinoid receptors and its molecular targets have not been defined. Here we show that OEA binds with high affinity to the peroxisome-proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor that regulates several aspects of lipid metabolism. Administration of OEA produces satiety and reduces body weight gain in wild-type mice, but not in mice deficient in PPAR-alpha. Two distinct PPAR-alpha agonists have similar effects that are also contingent on PPAR-alpha expression, whereas potent and selective agonists for PPAR-gamma and PPAR-beta/delta are ineffective. In the small intestine of wild-type but not PPAR-alpha-null mice, OEA regulates the expression of several PPAR-alpha target genes: it initiates the transcription of proteins involved in lipid metabolism and represses inducible nitric oxide synthase, an enzyme that may contribute to feeding stimulation. Our results, which show that OEA induces satiety by activating PPAR-alpha, identify an unexpected role for this nuclear receptor in regulating behaviour, and raise possibilities for the treatment of eating disorders.

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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 proteincoupled cannabinoid receptors. On the other hand, the monounsaturated FAE oleoylethanolamide (OEA) reduces feeding and body weight gain by activating the nuclear receptor PPAR-␣ (peroxisome proliferator-activated receptor ␣). In the present report, we examined whether OEA can also influence energy utilization. OEA (1-20 M) 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-␣ had been deleted by homologous recombination (PPAR-␣ ؊/؊ ). Likewise, OEA was unable to enhance lipolysis in adipocytes or stimulate fatty acid oxidation in skeletal muscle strips isolated from PPAR-␣ mice. The synthetic PPAR-␣ agonist Wy-14643 produced similar effects, which also were dependent on the presence of PPAR-␣. Subchronic treatment with OEA reduced body weight gain and triacylglycerol content in liver and adipose tissue of dietinduced obese rats and wild-type mice, but not in obese PPAR-␣ ؊/؊ mice. The results suggest that OEA stimulates fat utilization through activation of PPAR-␣ and that this effect may contribute to its anti-obesity actions.Amides of long-chain fatty acids with ethanolamine (FAE) 1 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 (1, 2). The FAE are hydrolyzed intracellularly to fatty acids and ethanolamine by the action of fatty acid amide hydrolase enzymes (3)(4)(5).Although the FAE were first described four decades ago (6), 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 ⌬ 9 -tetrahydrocannabinol (7). Anandamide is now established as a brain endocannabinoid messenger (8) and multiple roles for other FAE have also been proposed (9 -11). 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 (12). This action is of therapeutic relevance: cannabinoid agonists su...

Abstract. Oleoylethanolamide (OEA), the naturally occurring amide of ethanolamine and oleic acid, is an endogenous lipid that modulates feeding, body weight and lipid metabolism by binding with high affinity to the ligand-activated transcription factor, peroxisome proliferator-activated receptor-alpha (PPAR-a). In the CMLS, Cell. Mol. Life Sci. 62 (2005) 708 -716 1420-682X/05/060708-09 DOI 10.1007/s00018-004-4494-0 © Birkhäuser Verlag, Basel, 2005 CMLS Cellular and Molecular Life Sciencespresent article, we describe the biochemical pathways responsible for the initiation and termination of OEA signaling, and outline the pharmacological properties of this compound in relation to its ability to activate PPARa. Finally, we discuss the possible role of OEA as a peripheral satiety hormone.

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