Fu Jin, Gaetani Silvana, Oveisi Fariba, Lo Verme Jesse, Serrano Antonia, Rodríguez De Fonseca Fernando, Rosengarth Anja, Luecke Hartmut, Di Giacomo Barbara, Tarzia Giorgio, Piomelli Daniele
Department of Pharmacology, University of California, Irvine, California 92697-4625, USA.
Nature. 2003 Sep 4;425(6953):90-3. 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-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.
油酰乙醇胺（OEA）是一种天然存在的脂质，可调节饱腹感和体重。尽管OEA在结构上与内源性大麻素花生四烯酸乙醇胺相关，但它不与大麻素受体结合，其分子靶点也尚未明确。在此我们表明，OEA与过氧化物酶体增殖物激活受体α（PPAR-α）具有高亲和力结合，PPAR-α是一种调节脂质代谢多个方面的核受体。给野生型小鼠施用OEA可产生饱腹感并减少体重增加，但在缺乏PPAR-α的小鼠中则不然。两种不同的PPAR-α激动剂具有类似的效果，且这些效果也取决于PPAR-α的表达，而PPAR-γ和PPAR-β/δ的强效和选择性激动剂则无效。在野生型小鼠而非PPAR-α基因敲除小鼠的小肠中，OEA调节多个PPAR-α靶基因的表达：它启动参与脂质代谢的蛋白质的转录，并抑制诱导型一氧化氮合酶，该酶可能有助于刺激进食。我们的结果表明OEA通过激活PPAR-α诱导饱腹感，确定了这种核受体在调节行为中的意外作用，并为饮食失调的治疗带来了可能性。
