Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α
Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α
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DOI：
10.1038/nature01921
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发表时间：
2003-09-04
期刊：
影响因子：
64.8
通讯作者：
Piomelli, D
中科院分区：
文献类型：
--
作者：
Fu, J;Gaetani, S;Piomelli, D
油乙醇胺（OEA）是一种天然存在的脂质，可调节饱腹感和体重（1，2）。虽然在结构上与内源性大麻素anandamide相关，但OEA不与大麻素受体结合，其分子靶点尚未确定。在这里，我们表明OEA与过氧化物酶体增殖物激活受体-α（PPAR-alpha）具有高亲和力结合，PPAR-alpha是一种调节脂质代谢多个方面的核受体。OEA的施用在野生型小鼠中产生饱腹感并减少体重增加，但在PPAR-alpha缺陷的小鼠中不产生饱腹感和体重增加。两种不同的PPAR-alpha激动剂具有相似的作用，也取决于PPAR-alpha表达，而PPAR-gamma和PPAR-beta/delta的有效和选择性激动剂是无效的。在野生型而不是PPAR-alpha-null小鼠的小肠中，OEA调节几种PPAR-alpha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，这是一种可能有助于摄食刺激的酶。我们的研究结果表明，OEA通过激活PPAR-alpha诱导饱腹感，确定了这种核受体在调节行为中的意外作用，并提高了治疗饮食失调的可能性。
Oleylethanolamide (OEA) is a naturally occurring lipid that regulates satiety and body weight(1,2). 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-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.