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

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.

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Figure 1: OEA is a high-affinity PPAR-α agonist.
Figure 2: PPAR-α mediates the appetite-suppressing and weight-reducing effects of OEA.
Figure 3: PPAR-α agonists mimic the appetite-suppressing effects of OEA.
Figure 4: OEA regulates gene expression through PPAR-α activation.
Figure 5: Circadian regulation of intestinal OEA synthesis and PPAR-α expression.

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Acknowledgements

We thank L. Stein for comments; L. Giron, N. Heyrani, N. Izadi and K. Nguyen for help with experiments; M. Guzmán for critically reading the manuscript; and F. Valiño for synthesizing fatty acid ethanolamides. This research was supported by grants (to D.P.) from the National Institute on Drug Abuse. Further support came from the Fondo de Investigación Sanitaria.

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Correspondence to Daniele Piomelli.

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A patent application on this subject been filed on behalf of the University of California Irvine.

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Supplementary Information: Methods (PDF 63 kb)

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