有氧运动调控肥胖小鼠棕色脂肪组织炎症反应相关基因表达及通路的研究

Studies on Aerobic Exercise Modulating Genes and Pathways Associated with Inflammation of Brown Adipose Tissue in Obese Mice

目的:应用m RNA表达谱芯片技术探究有氧运动对肥胖小鼠棕色脂肪组织(BAT)炎症反应相关差异基因和通路表达的影响。方法:30只雄性C57BL/6J小鼠随机分为普通饮食对照组(NC,n=8)和高脂饮食组(HD,n=22),高脂饮食组饲喂8周建立肥胖模型后再随机分为肥胖安静对照组(HC,n=8)和肥胖运动组(HE,n=8)。NC组饲喂普通饲料;HC组饲喂高脂饲料;HE组饲喂高脂饲料的同时进行10 m/min,1 h/d,6 d/w的跑台训练。4周后,测试血中甘油三酯、总胆固醇和血糖水平;取肩胛处BAT进行m RNA表达谱分析,分别对比HC与NC组、HE与HC组的差异表达基因,并对其进行基因功能注释(GO)和信号通路(Pathway)富集度统计分析。结果:(1)HE组较HC组体重和血糖水平显著下降(P<0.05);(2)差异基因筛选和GO分析结果显示,HC组较NC组上调的基因有802个,包含的生物学过程(BP)主要为炎症反应等过程;下调的基因有1157个,BP主要为脂质代谢等过程;HE与HC组相比上调的基因有859个,BP主要为糖脂代谢等过程,下调的基因有576个,BP主要为转录调节等过程。巨噬细胞表达基因1(Mpeg1)、单核细胞向巨噬细胞转化基因(Mmd)、趋化因子配体28(Ccl28)、白介素-6受体α(IL6ra)、肿瘤坏死因子受体超家族成员1b(Tnfrsf1b)、瘦素受体(Lepr)6个与免疫细胞及炎症因子相关的关键差异基因在运动后出现下调或有下调趋势;(3)Pathway分析结果显示,与HC组相比,HE组Jak-STAT信号通路、Erb B信号通路和TGF-β信号通路显著下调,Insulin信号通路显著上调。结论:有氧运动可通过调节肥胖机体BAT中一系列生物学过程和信号通路而抑制免疫细胞和炎症因子相关基因表达,改善肥胖机体慢性炎症状态。

Objective To explore the effect of aerobic exercise on the expression of differentially ex-pressed genes and pathways related to the inflammatory response of the brown adipose tissue（BAT） inobese mice using the m RNA expression profiling microarray. Methods Thirty male C57 BL/6 J mice wererandomly divided into a normal control group（NC,n=8） and a high-fat diet group（HD,n=22）. The obe-sity model was establish in the HD group after 8-week high-fat diet feeding,before the HD group wasfurther divided into a high-fat diet control group（HC,n=8） and a high-fat diet exercise group（HE,n=8）. The NC and HC group were fed with normal and high-fat diet respectively without any exercises,while the HE group underwent 1-hour treadmill training every day at 10 m/min,six days a week. Thetriglyceride,total cholesterol and blood glucose level were tested after 4-week intervention. The totalRNA in BAT from the scapular area was scanned using m RNA expression profile chip and given bioinformatics analysis. Differential genes were conducted gene ontology（GO） and pathway enrichment analy-sis and compared between group HC and NC,group HE and HC. Results Compared with the HCgroup,significant decrease was observed in the body weight and blood glucose levels of the HE group（P〈0.05）. Compared with the NC group,802 genes related to the inflammatory response were signifi-cantly up-regulated,and 1157 genes related to the lipid metabolism were down-regulated in the HCgroup. In the HE group,859 genes mainly involved in the glycolipid metabolism were significantly up-regulated,while 576 genes related to the transcriptional regulation were down-regulated compared withgroup HC. Six key differential genes related to the inflammation,including the macrophage expressedgene 1,monocyte to macrophage differentiation-associated,chemokine（C-C motif） ligand 28,interleukin6 receptor alpha,tumor necrosis factor receptor superfamily,member 1 b and leptin receptor were foundto decrease or have the tendency of decreasing after the treadmill training. The pathway analysisshowed that compared with the HC group,the Jak-STAT signaling pathway,Erb B signaling pathway andTGF-β signaling pathway were significantly down-regulated in group HE,while the insulin signalingpathway was significantly up-regulated. Conclusion Aerobic exercise can inhibit the expression ofgenes related to immune cells and pro-inflammatory cytokines genes expressions by regulating a seriesof biological processes and pathways in BAT to improve the chronic inflammatory state of the obesebody.