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

By Jin Fu, S. Gaetani, F. Oveisi, J. Verme, A. Serrano, F. R. Fonseca, A. Rosengarth, H. Luecke, B. D. Giacomo, G. Tarzia and 1 more. Nature, 2003

1,092 citations recorded by the source corpus.

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.

Subfields: Endocrinology, Diabetes and Metabolism, Molecular Biology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/291e7240289e32f06e1bb7a81c7de2b933044379

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Daniele Piomelli
2. R. Ross
3. R. Pertwee

In Pharmacology

1. R. Pertwee
2. V. Di Marzo
3. George Kunos
4. P. Pacher
5. S. Batkai
6. K. Mackie
7. R. Ross
8. R. Mechoulam

Citations in the corpus

• The Endocannabinoid System as an Emerging Target of Pharmacotherapy (2006, background): “…the targeting of FAAH in the treatment of eating/metabolic disorders, such an approach will be complicated by the fact that oleylethanolamide, an anorectic lipid that acts on the peroxisome proliferatorproliferator-activated receptor α (PPARα) (Fu et al., 2003), is also a substrate for FAAH.”
• Integrated physiology and systems biology of PPARα (2014, neutral): “[122] Fu, J.”
• International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2 (2010, background): “…in COS cells expressing recombinant receptors (Bouaboula et al., 2005). c EC 50 reporter gene assay in HeLa cells expressing recombinant receptors (Fu et al., 2003). d EC 50 reporter gene assay in MCF7 cells expressing recombinant receptors (Alvarado et al., 2008). e IC 50…”
• The emerging role of the endocannabinoid system in endocrine regulation and energy balance. (2006, background): “OEA not only acts as a satiety signal, but also reduces body weight gain and serum lipid levels in genetically obese rats and in DIO mice (318).”
• The Nuclear Receptor Peroxisome Proliferator-Activated Receptor-α Mediates the Anti-Inflammatory Actions of Palmitoylethanolamide (2005, methodology): “To test this possibility, we assessed the effects of PEA administration on PPAR- mRNA levels, which are known to be up-regulated by PPAR- agonists (Fu et al., 2003).”
• The molecular logic of endocannabinoid signalling (2003, background): “Particularly notable is FAAH's ability to hydrolyse bioactive fatty amides, which do not bind to any of the known cannabinoid receptors: these include the satiety factor oleoylethanolamid”