奥氮平诱导体重增加小鼠的全脑转录组学分析  

Whole-brain Transcriptomic Analysis of Weight Gain Mice induced by Olanzapine

作　　者：张渊 李晗[2] 张成芳 ZHANG Yuan;LI Han;ZHANG Chengfang(Clinical Research Center for Mental Disorders,Shanghai Pudong New Area Mental Health Center,School of Medicine,Tongji University,Shanghai 200124,China;Shanghai Mental Health Center,Shanghai Jiao Tong University of Medicine,Shanghai Key Laboratory of Psychotic Disorders,Shanghai 201108,China)

机构地区：[1]同济大学附属精神卫生中心(上海市浦东新区精神卫生中心),同济大学精神疾病临床研究中心,上海200124 [2]上海交通大学医学院附属精神卫生中心,上海市重性精神病重点实验室,上海201108

出　　处：《实验动物与比较医学》2023年第3期262-270,共9页Laboratory Animal and Comparative Medicine

基　　金：上海市浦东新区优秀青年医学人才培养计划“基于全脑转录组测序筛选奥氮平调控小鼠中枢摄食网络的关键基因”(PWRq2020-19);上海市浦东新区精神卫生中心院级科研面上项目“稳定期精神分裂症患者外周血氧化应激与认知功能相关性分析”(PDJWM202002)。

摘　　要：目的分析奥氮平给药组与对照组的小鼠脑组织的转录组测序结果,筛选出差异表达基因,探索非典型抗精神病药奥氮平导致体重增加的潜在作用靶点。方法20只雌性C57BL/6小鼠被随机分为对照组和奥氮平给药组,分别给予生理盐水和奥氮平溶液灌胃,8周后留取全脑组织进行转录组测序(transcriptome sequencing,RNA-Seq)。通过对测序结果进行基因本体论(gene ontology,GO)功能注释分析和基因组百科全书(Kyoto encyclopedia of genes and gnomes,KEGG)途径富集分析以及蛋白互作(protein-protein interaction,PPI)网络分析等,寻找奥氮平诱导体重增加的可能靶点,并通过实时荧光定量PCR法进行验证。结果对照组和奥氮平给药组的差异表达基因共591个,其中上调基因251个,下调基因340个。GO分析显示差异基因广泛参与转录过程,其中消化系统的调节和冷诱导的产热相关基因表达属于显著富集项目。KEGG分析显示差异基因广泛参与神经活性物质与受体之间的相互作用,差异基因显著富集在催产素信号、脂肪的消化吸收以及胆固醇代谢通路。实时荧光定量PCR结果表明,富集在摄食调控、胃运动、产热、脂肪代谢等过程的基因(Oxt、Trpv1、Adipoq、Phox2b、Abcg5、Mogat2、Dbh、Plac8、Neurog1)以及PPI网络中的枢纽基因(Fos、Dusp1、Egr2)的表达改变与RNA-Seq趋势一致。结论奥氮平给药导致小鼠中枢的摄食调控、胃肠运动、产热等生理过程发生改变,这些改变可能参与了奥氮平诱导的体重增加。Objective The transcriptome sequencing results of brain tissues of olanzapine-treated mice were analyzed to screen out differentially-expressed genes and explore potential targets of atypical antipsychotics leading to body weight gain.Methods Twenty female C57BL/6 mice were randomly divided into control group(Ctrl)and Olanzapine administration group(Olz),which were given saline and Olanzapine solution by gavage,respectively.The whole brain tissues were collected 8 weeks later for Transcriptome sequencing(RNA-Seq).The possible targets of olanzapine-induced body weight gain were identified by the Gene Ontology(GO)functional annotation analysis,the Kyoto Encyclopedia of Genes and Gnomes(KEGG)pathway enrichment analysis,and protein-protein interaction(PPI)network analysis.Differential expression levels of mRNAs were further verified by real-time quantitative fluorescence PCR(RT-qPCR).Results Compared with Ctrl group,591 differentially expressed genes were screened in Olz group,including 251 upregulated genes and 340 down-regulated genes.GO analysis showed that differential genes were widely involved in transcriptional process,among which the expression of genes related to the regulation of digestive system and cold-induced thermogenesis were significantly enriched.KEGG analysis showed that differential genes were widely involved in the interaction between neuroactive ligands and receptors,and the differential genes were significantly enriched in oxytocin signaling,fat digestion and absorption,and cholesterol metabolism pathways.RT-qPCR were performed to verify the expression levels of genes enriched in feeding regulation,gastric kinesis,thermogenesis,fat metabolism and other processes(Oxt,Trpv1,Adipoq,Phox2b,Abcg5,Mogat2,Dbh,Plac8 and Neurog1)as well as hub genes in PPI network(Fos,Dusp1 and Egr2),and the results were consistent with the trend of RNA-Seq.Conclusion Olanzapine administration resulted in changes in central feeding regulation,gastrointestinal motility,thermogenesis and other physiological processes in m

关 键 词：奥氮平 体重增加 全脑 转录组测序 小鼠 

分 类 号：R-332[医药卫生] Q95-33[生物学—动物学]