奥氮平多靶点激活H1R-AMPK通路导致药源性肥胖  

Olanzapine Induced Obesity via Multiple-site Activation of H1R-AMPK Signaling

作　　者：张颖 李文婷 黄旭枫 钱琨 何梦 孙涛垒 ZHANG Ying;LI Wen-ting;HUANG Xu-feng;QIAN Kun;HE Meng;SUN Tao-lei(School of Chemistry,Chemical Engineering and Life Sciences,Wuhan University of Technology,Wuhan 430070,China;Illawarra Health and Medical Research Institute and Centre for Translational Neuroscience,School of Medicine,University of Wollongong,Wollongong 2522,Australia)

机构地区：[1]武汉理工大学化学化工与生命科学学院,武汉430070 [2]伍伦贡大学医学院伊拉瓦拉卫生与医学研究所和转化神经科学中心,伍伦贡2522

出　　处：《武汉理工大学学报》2020年第4期18-25,98,共9页Journal of Wuhan University of Technology

基　　金：国家自然科学基金(81803515);湖北省自然科学基金(2018CFB342);武汉理工大学自主创新基金(193220005)。

摘　　要：抗精神病药物所致肥胖是长期困扰临床医师和患者的一大难题。本项目研究奥氮平"多靶点"导致肥胖的共同通路。用蛋白质免疫印迹法在奥氮平肥胖大鼠模型中检测急性及短期奥氮平给药对下丘脑内侧基底部(Medial basal hypothalamus,MBH),室旁核和迷走神经复合体(Dorsal vagal complex of brainstem,DVC)内组胺H1受体(H1 receptor,H1R)-腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)通路的调控规律,分析其与肥胖的关系。单次奥氮平给药未增加动物摄食,但显著激活MBH及DVC内H1R-AMPK信号通路,奥氮平给药3d增加动物摄食及体重,同时激活H1R-AMPK信号通路。AMPK磷酸化与动物体重呈显著正相关。奥氮平多靶点激活H1R-AMPK信号通路,该通路激活早于肥胖的发生,是动物肥胖的关键原因,多靶点抑制该通路对治疗奥氮平所致肥胖有重要意义。This project investigated the common pathways of olanzapine induced obesity in multiple brain regions.Western blot analysis was used to investigate the effect of acute and short-term olanzapine treatment on histamine H1 receptorAMPK activated protein kinase(H1R-AMPK)signaling in the medial base hypothalamus(MBH),paraventricular hypothalamus and brainstem dorsal vagal complex(DVC)in an olanzapine-induced obese rat model.A single injection of olanzapine did not induce hyperphagia but activated the H1R-AMPK signaling in MBH and DVC.3-day olanzapine injection induce hyperphagia and weight gain,accompanied by activated H1R-AMPK signaling.Phosphor-AMPK was significantly correlated with weight gain.Olanzapine activated H1R-AMPK signaling in multiple-sites and these effects occurred earlier than weight gain onset.Multi-target inhibition of this pathway is of great significance for the treatment of obesity caused by olanzapine.

关 键 词：奥氮平 肥胖 下丘脑内侧基底部 脑干背侧迷走神经复合体 H1受体-AMPK信号通路 

分 类 号：R749.3[医药卫生—神经病学与精神病学]