Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance.
Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance.
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DOI：
10.1016/j.cmet.2012.07.002
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发表时间：
2012-08-08
期刊：
影响因子：
29
通讯作者：
Kunos G
中科院分区：
文献类型：
--
作者：
Tam J;Cinar R;Liu J;Godlewski G;Wesley D;Jourdan T;Szanda G;Mukhopadhyay B;Chedester L;Liow JS;Innis RB;Cheng K;Rice KC;Deschamps JR;Chorvat RJ;McElroy JF;Kunos G
肥胖相关的瘦素抵抗表现为瘦素减少食欲和增加能量消耗的能力的丧失。肥胖也与内源性大麻素系统的活性增加有关，而CB1受体（CB1R）逆激动剂可以减少体重和相关的代谢并发症，尽管不良的神经精神效应阻止了其治疗发展。在饮食性肥胖（DIO）小鼠中，外周限制性CB1R逆激动剂JD5037与其脑渗透母体化合物在减少食欲、体重、肝脂肪变性和胰岛素抵抗方面是同等有效的，即使它不占据中枢CB1R或诱导相关行为。JD5037通过降低脂肪细胞的瘦素表达和分泌以及通过肾脏增加瘦素清除率来逆转高瘦素血症，从而使DIO小鼠对内源性瘦素重敏，从而减轻食欲和体重。因此，外周CB1R的拮抗作用不仅可以改善肥胖患者的心脏代谢风险，还可以通过逆转瘦素抵抗而起到抗肥胖作用。
Obesity-related leptin resistance manifests in loss of leptin’s ability to reduce appetite and increase energy expenditure. Obesity is also associated with increased activity of the endocannabinoid system, and CB1 receptor (CB1R) inverse agonists reduce body weight and the associated metabolic complications, although adverse neuropsychiatric effects halted their therapeutic development. Here we show that in mice with diet-induced obesity (DIO), the peripherally restricted CB1R inverse agonist JD5037 is equieffective with its brain-penetrant parent compound in reducing appetite, body weight, hepatic steatosis, and insulin resistance, even though it does not occupy central CB1R or induce related behaviors. Appetite and weight reduction by JD5037 are mediated by resensitizing DIO mice to endogenous leptin through reversing the hyperleptinemia by decreasing leptin expression and secretion by adipocytes and increasing leptin clearance via the kidney. Thus, inverse agonism at peripheral CB1R not only improves cardiometabolic risk in obesity but has antiobesity effects by reversing leptin resistance.
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通讯作者：
Kunos G