Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α

• Published in: Nature 2003-09, Vol.425 (6953), p.90-93
• Main Authors: Piomelli, Daniele, Fu, Jin, Gaetani, Silvana, Oveisi, Fariba, Lo Verme, Jesse, Serrano, Antonia, Rodríguez de Fonseca, Fernando, Rosengarth, Anja, Luecke, Hartmut, Di Giacomo, Barbara, Tarzia, Giorgio
• Format: Article
• Language: English
• Subjects: Animals; Appetite Depressants - metabolism; Appetite Depressants - pharmacology; Biological and medical sciences; Body weight; Body Weight - drug effects; Circadian Rhythm - physiology; Eating disorders; Feeding Behavior - drug effects; Food; Gene Deletion; Gene Expression Regulation - drug effects; General and cellular metabolism. Vitamins; HeLa Cells; Humanities and Social Sciences; Humans; Intestines - metabolism; letter; Lipid Metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Neurotransmitters; Nitric oxide; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type II; Oleic Acid - biosynthesis; Oleic Acid - metabolism; Oleic Acid - pharmacology; Oleic Acids; Pharmacology. Drug treatments; Protein Binding; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Science; Science (multidisciplinary); Transcription Factors - agonists; Transcription Factors - genetics; Transcription Factors - metabolism; Weight
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature01921

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-α (PPAR-α), 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-α. Two distinct PPAR-α agonists have similar effects that are also contingent on PPAR-α expression, whereas potent and selective agonists for PPAR-γ and PPAR-β/δ are ineffective. In the small intestine of wild-type but not PPAR-α-null mice, OEA regulates the expression of several PPAR-α 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-α, identify an unexpected role for this nuclear receptor in regulating behaviour, and raise possibilities for the treatment of eating disorders.