Differential Expression of MicroRNAs in Omental Adipose Tissue From Gestational Diabetes Mellitus Subjects Reveals miR-222 as a Regulator of ERα Expression in Estrogen-Induced Insulin Resistance
Differential Expression of MicroRNAs in Omental Adipose Tissue From Gestational Diabetes Mellitus Subjects Reveals miR-222 as a Regulator of ERα Expression in Estrogen-Induced Insulin Resistance
复制标题
DOI：
10.1210/en.2013-2046
复制
发表时间：
2014-05-01
期刊：
影响因子：
4.8
通讯作者：
Liu, Jiayin
中科院分区：
文献类型：
--
作者：
Shi, Zhonghua;Zhao, Chun;Liu, Jiayin
大网膜脂肪组织在妊娠糖尿病（GDM）的胰岛素抵抗中发挥着核心作用，但导致 GDM 的分子机制仍不清楚。有证据表明，雌二醇等母体激素会导致妊娠期糖尿病 (GDM) 的胰岛素抵抗。在本研究中，我们使用 AFFX miRNA 表达芯片确定了 GDM 患者和糖耐量正常孕妇的网膜脂肪组织中 microRNA (miRNA) 的差异表达模式。通过实时定量 PCR 发现 MiR-222 是 17 个差异表达 miRNA 中的一个，在 GDM 中显着上调 (P < .01)，并且其表达与血清雌二醇水平密切相关 (P < .05)。此外，高浓度 17β-雌二醇刺激的 3T3-L1 脂肪细胞中 miR-222 表达显着增加 (P < .01)，而雌激素受体 (ER)-α 蛋白和胰岛素敏感膜转运蛋白葡萄糖转运蛋白 4 (GLUT4) 蛋白的表达显着降低 (P < .01)。此外，通过使用荧光素酶测定，ER α 被证明是 3T3-L1 脂肪细胞中 miR-222 的直接靶标。最后，使用miR-222转染的反义寡核苷酸沉默3T3-L1脂肪细胞中的miR-222。结果显示，成熟脂肪细胞中 ER α 和 GLUT4 的表达、胰岛素刺激的 GLUT4 从细胞质到细胞膜的易位以及葡萄糖摄取均显着增加 (P < .01)。总之，miR-222是GDM雌激素诱导的胰岛素抵抗中ERα表达的潜在调节因子，并且可能是GDM的候选生物标志物和治疗靶点。
Omental adipose tissue plays a central role in insulin resistance in gestational diabetes mellitus (GDM), and the molecular mechanisms leading to GDM remains vague. Evidence demonstrates that maternal hormones, such as estradiol, contribute to insulin resistance in GDM. In this study we determined the differential expression patterns of microRNAs (miRNAs) in omental adipose tissues from GDM patients and pregnant women with normal glucose tolerance using AFFX miRNA expression chips. MiR-222, 1 of 17 identified differentially expressed miRNAs, was found to be significantly up-regulated in GDM by quantitative real-time PCR (P < .01), and its expression was closely related with serum estradiol level (P < .05). Furthermore, miR-222 expression was significantly increased in 3T3-L1 adipocytes with a high concentration of 17 beta-estradiol stimulation (P < .01), whereas the expressions of estrogen receptor (ER)-alpha protein and insulin-sensitive membrane transporter glucose transporter 4 (GLUT4) protein (P < .01) were markedly reduced. In addition, ER alpha was shown to be a direct target of miR-222 in 3T3-L1 adipocytes by using the luciferase assay. Finally, antisense oligonucleotides of miR-222 transfection was used to silence miR-222 in 3T3-L1 adipocytes. The results showed that the expressions of ER alpha and GLUT4, the insulin-stimulated translocation of GLUT4 from the cytoplasm to the cell membrane and glucose uptake in mature adipocytes were dramatically increased (P < .01). In conclusion, miR-222 is a potential regulator of ER alpha expression in estrogen-induced insulin resistance in GDM and might be a candidate biomarker and therapeutic target for GDM.