Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity
Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity
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DOI：
10.1172/jci200523057
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发表时间：
2005-05-01
影响因子：
15.9
通讯作者：
Kunos, G
中科院分区：
文献类型：
--
作者：
Osei-Hyiaman, D;DePetrillo, M;Kunos, G
作用于CB受体的内源性大麻素刺激食欲，CB拮抗剂在治疗肥胖中显示出希望。CB 1-/-小鼠对饮食诱导的肥胖有抵抗力，即使它们的热量摄入与野生型小鼠相似，这表明内源性大麻素也调节脂肪代谢。在这里，我们研究了内源性大麻素在调节肝脏脂肪生成中的可能作用。小鼠中CB 1的激活增加了脂肪生成转录因子SR-EBP-1c及其靶标乙酰辅酶A羧化酶-1和脂肪酸合成酶（FAS）的肝脏基因表达。用CB 1激动剂治疗还增加肝脏或表达CB 1的分离的肝细胞中的从头脂肪酸合成。高脂饮食增加内源性大麻素anandamide（花生四烯酸乙醇酰胺），CB 1密度和脂肪酸合成的基础速率的肝脏水平，后者通过CB 1阻断降低。在FAS抑制剂引起厌食的下丘脑中，SREBP-1c和FAS表达同样受到CB 1配体的影响。我们得出结论，花生四烯酸作用于肝脏CBI有助于饮食诱导的肥胖，FAS途径可能是中枢食欲和外周代谢调节的共同分子靶点。
Endogenous cannabinoids acting at CB, receptors stimulate appetite, and CB, antagonists show promise in the treatment of obesity. CB1-/- mice are resistant to diet-induced obesity even though their caloric intake is similar to that of wild-type mice, suggesting that endocannabinoids also regulate fat metabolism. Here, we investigated the possible role of endocannabinoids in the regulation of hepatic lipogenesis. Activation of CB1 in mice increases the hepatic gene expression of the lipogenic transcription factor SR-EBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase (FAS). Treatment with a CB1 agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, which express CB1. High-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB1 density, and basal rates of fatty acid synthesis, and the latter is reduced by CB1 blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP-1c and FAS expression are similarly affected by CB1 ligands. We conclude that anandamide acting at hepatic CBI contributes to diet-induced obesity and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation.