SH2B1调控JAK2/IRS2在肥胖症发病中的分子机制  

Molecular mechanism of SH2B1 in regulating JAK2/IRS2 during obesity development

作　　者：段朝军[1,2] 汤参娥[1,2] 廖岚 李萃 苏涛[1] 陈主初 

机构地区：[1]中南大学湘雅医院卫生部肿瘤蛋白质组学重点实验室,长沙410008 [2]医学实验研究中心,长沙410008 [3]内分泌科,长沙410008

出　　处：《中南大学学报（医学版）》2010年第3期209-214,共6页Journal of Central South University ：Medical Science

基　　金：国家自然科学基金(30670990,30871189)~~

摘　　要：目的:研究JAK2接头蛋白SH2B1调控JAK2/IRS2在肥胖症发病中的作用及其分子机制。方法:采用高效稳定表达瘦素受体的细胞株HEK239LRb和SH2B1基因缺失小鼠,Western印迹、[γ-32P]-ATP体外激活分析法分析瘦素信号通路关键分子JAK2和IRS2的酪氨酸磷酸化水平;ELISA法测定小鼠血清瘦素水平;检测出生后至27周小鼠体质量。结果:在高效稳定表达瘦素受体细胞株HEK239LRb中,SH2B13显著增强瘦素刺激的JAK2激酶活性和IRS2磷酸化;在SH2B1基因缺失小鼠中,瘦素刺激JAK2激酶活性和IRS2酪氨酸磷酸化水平均显著降低;无论空腹还是随机给食,SH2B1基因缺失小鼠血清瘦素水平均升高并发展为高瘦素血症,其血清瘦素水平与同窝野生型小鼠相比分别增加3.2倍和5.1倍。5周后,SH2B1基因缺失小鼠体质量逐渐增加,21周龄时,大约为同窝野生型小鼠2倍。结论:JAK2接头蛋白SH2B1是内源性瘦素敏感性增强子,通过瘦素JAK2/IRS2信号通路参与瘦素对体质量的调节,SH2B1基因缺失小鼠易发展为高瘦素血症及肥胖。Objective In order to investigate the effect of SH2B1 on leptin signal transduction JAK2/IRS2 and its biological function.Methods Vitro kinase assay and Western blot were used to analyse tyrosine phosphorylatin of key molecule JAK2 and insulin receptor substrate-2（IRS2）.ELISA was used to measure the plasma leptin levels in mice.The postnatal growth of mice was monitored over 27 weeks.Results SH2B1 dramatically enhanced the leptin-stimulated tyrosine phosphorylation of JAK2 and IRS2 in HEK293 cells stably expressing LRb（HEK239LRb）.Leptin-stimulated activation of hypothalamic JAK2 and phosphorylation of hyphothalamic IRS2 were significantly impaired in SH2B1-/-mice.The deletion of SH2B1 led to leptin resistance,and fasting and randomly fed plasma leptin levels were respectively 3.2 times and 5.1 times higher in SH2B1-/-males than wild-type littermates at 15 weeks of age.SH2B1-/-males gained body weight rapidly and exceeded wild-type littermates from 5th week.SH2B1-/-（at 21 weeks）was approximately twice heavier than wild-type littermates.Conclusion SH2B1 is an endogenous enhancer of leptin sensitivity and required for maintaining normal bodyweight in mice via leptin JAK2/IRS2 pathway.

关 键 词：SH2B1 肥胖症 胰岛素受体底物-2 瘦素信号通路 

分 类 号：R589.2[医药卫生—内分泌]