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

Jin Fu, Silvana Gaetani, Fariba Oveisi, Jesse Lo Verme, Antonia Serrano, Fernando Rodríguez de Fonseca, Anja Rosengarth, Hartmut Luecke, Barbara Di Giacomo, Giorgio Tarzia and Daniele Piomelli ()
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Jin Fu: University of California
Silvana Gaetani: University of California
Fariba Oveisi: University of California
Jesse Lo Verme: University of California
Antonia Serrano: Fundación Hospital Carlos Haya
Fernando Rodríguez de Fonseca: Fundación Hospital Carlos Haya
Anja Rosengarth: University of California
Hartmut Luecke: University of California
Barbara Di Giacomo: University of Urbino
Giorgio Tarzia: University of Urbino
Daniele Piomelli: University of California

Nature, 2003, vol. 425, issue 6953, 90-93

Abstract: Abstract Oleylethanolamide (OEA) is a naturally occurring lipid that regulates satiety and body weight1,2. 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.

Date: 2003
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DOI: 10.1038/nature01921

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