Nakaoka Hirotomo, Mogi Masaki, Kan-No Harumi, Tsukuda Kana, Ohshima Kousei, Wang Xiao-Li, Chisaka Toshiyuki, Bai Hui-Yu, Shan Bao-Shuai, Kukida Masayoshi, Iwanami Jun, Horiuchi Masatsugu
Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Japan.
Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Japan
J Renin Angiotensin Aldosterone Syst. 2015 Dec;16(4):749-57. doi: 10.1177/1470320315573680. Epub 2015 Mar 9.
Binge eating disorder (BED) is associated with dopaminergic activation as food reward, resulting in metabolism-related disorders. Stimulation of angiotensin type 2 (AT2) receptor is reported to inhibit dopamine synthesis. We investigated the possible roles of AT2 receptor-mediated dopamine regulation in the pathogenesis of BED.
Male C57BL/6 mice, type 2 diabetic (KKAy) mice and AT2 receptor-null (AT2KO) mice at eight weeks old were treated with AT2 receptor agonist, compound 21 (C21) or saline for two weeks. Mice were subjected to fasting for two days followed by re-feeding for seven days.
Treatment with C21 attenuated the rebound proportion of body weight, food intake and water intake in KKAy mice, but not in C57BL/6 and AT2KO mice. Dopamine concentration in the striatum was further increased by fasting in KKAy and AT2KO mice. Administration of C21 significantly attenuated this fasting-induced increase in dopamine level only in KKAy mice. Dopamine receptor D1, D2 expression in the substantia nigra were markedly lower in KKAy mice compared with C57BL/6 mice, while administration of C21 increased their expression in KKAy mice.
Our study suggests that AT2 receptor stimulation may be a new therapeutic approach to improve eating disorder associated with dopamine resistance.
暴饮暴食症（BED）与作为食物奖励的多巴胺能激活有关，会导致代谢相关疾病。据报道，刺激2型血管紧张素（AT2）受体可抑制多巴胺合成。我们研究了AT2受体介导的多巴胺调节在BED发病机制中的可能作用。
对8周龄的雄性C57BL/6小鼠、2型糖尿病（KKAy）小鼠和AT2受体基因敲除（AT2KO）小鼠，用AT2受体激动剂化合物21（C21）或生理盐水处理两周。小鼠禁食两天，然后再喂食七天。
用C21处理可减轻KKAy小鼠体重、食物摄入量和饮水量的反弹比例，但对C57BL/6小鼠和AT2KO小鼠无效。禁食使KKAy小鼠和AT2KO小鼠纹状体中的多巴胺浓度进一步升高。仅在KKAy小鼠中，给予C21可显著减轻这种禁食诱导的多巴胺水平升高。与C57BL/6小鼠相比，KKAy小鼠黑质中的多巴胺受体D1、D2表达明显较低，而给予C21可增加KKAy小鼠中它们的表达。
我们的研究表明，刺激AT2受体可能是改善与多巴胺抵抗相关的饮食失调的一种新治疗方法。
