Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha.
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.
Fu
Jin
J
Department of Pharmacology, University of California, Irvine, California 92697-4625, USA.
Gaetani
Silvana
S
Oveisi
Fariba
F
Lo Verme
Jesse
J
Serrano
Antonia
A
Rodríguez De Fonseca
Fernando
F
Rosengarth
Anja
A
Luecke
Hartmut
H
Di Giacomo
Barbara
B
Tarzia
Giorgio
G
Piomelli
Daniele
D
D000818:Animals; D001067:Appetite Depressants / Q000378:metabolism / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects*; D002940:Circadian Rhythm / Q000502:physiology; D005247:Feeding Behavior / Q000187:drug effects*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D019301:Oleic Acid / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology*; D009829:Oleic Acids; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
D001067:Appetite Depressants; D009829:Oleic Acids; C440229:Oleylethanolamide; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019301:Oleic Acid; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse