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

Abstract

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 17β-estradiol stimulation (P < .01), whereas the expressions of estrogen receptor (ER)-α protein and insulin-sensitive membrane transporter glucose transporter 4 (GLUT4) protein (P < .01) were markedly reduced. In addition, ERα 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 ERα 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 ERα expression in estrogen-induced insulin resistance in GDM and might be a candidate biomarker and therapeutic target for GDM.

Transgenic Expression of miR-222 Disrupts Intestinal Epithelial Regeneration by Targeting Multiple Genes Including Frizzled-7

“…However, this study was conducted in cultured IECs, and miR-222 has been considered to act as a tumor suppressor or oncogene in cancer development (12,(21)(22)(23); therefore, the exact function of miR-222 in the intestinal epithelium in vivo remains to be fully investigated. By using a tissue-specific transgenic expression approach, here we provided powerful genetic evidence that miR-222 plays an important role in the regulation of intestinal mucosal regeneration and protection.…”

“…miR-222 modulates distinct cellular functions (17)(18)(19), and its role in cancer development can be either tumor suppressive or oncogenic, depending on cellular content and tumor type (20,21). miR-222 in human colorectal cancer cells acts in a positive feedback loop to increase expression levels of RelA and STAT3 (22), but miR-222 is a potential repressor of estrogen receptor (ER)-α expression in 3T3-L1 adipocytes (23). Our previous studies indicate that miR-222 and the RNA-binding protein (RBP) CUGBP1/CELF1 (CUG triplet repeat, RNA binding protein 1/CUGBP Elav-like member 1) synergistically inhibit cyclindependent kinase 4 (CDK4) translation in normal IECs by recruiting the Cdk4 mRNA to processing bodies (12).…”

The role of sex steroids in white adipose tissue adipocyte function

“…Recent evidence suggests that ESR1 is a direct target of miR-222 with a specific site at the seed sequence of this miR (Rao et al 2011). Furthermore, high E2 concentrations in visceral adipocytes upregulate miR-222 transcript levels and downregulate Esr1 and Glut4 transcript levels (Shi et al 2014). By contrast, Esr2 has been found to control Glut4 transcription via DNA methylation in induced murine adipocytes (Rüegg et al 2011).…”

Integrated Transcriptome Sequencing Analysis Reveals Role of miR-138-5p/ TBL1X in Placenta from Gestational Diabetes Mellitus

“…miRNAs have been shown to participate in the carcinogenesis of several types of tumors, and they can impair cellular movement, invasion, growth and proliferation, thus promoting the development of tumors [42]. miRNAs are also expressed in the placenta and have been reported in pregnancy complications including GDM and preeclampsia [21,43]. Fu et al identified a series of miRNAs that were involved in dysregulated placental development and function [44].…”

“…Previous studies on trophoblasts have suggested that miRNAs are involved in proliferative, migratory and invasive processes [19]. Many differentially expressed miRNAs have been identified based on hybridization, qPCR, and sequencing analysis in the GDM placenta or serum [20,21]. Recently, Bari et al performed specific mRNA sequencing with trophoblast isolated from the GDM placenta and indicated that placental trophoblasts of GDM were biologically different from those in the control group at the gene expression level [22].…”