Gestational diabetes and maternal obesity are associated with sex-specific changes in miRNA and target gene expression in the fetus.,International Journal of Obesity

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Gestational diabetes and maternal obesity are associated with sex-specific changes in miRNA and target gene expression in the fetus.
International Journal of Obesity ( IF 4.2 ) Pub Date : 2019-12-18 , DOI: 10.1038/s41366-019-0485-y
Apoorva Joshi ₁ , Rikka Azuma ₁ , Rita Akumuo ₁ , Laura Goetzl ₂ , Sara E Pinney _{1,

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4,

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Affiliation

BACKGROUND/OBJECTIVES Pregnancies complicated by gestational diabetes (GDM) or maternal obesity have been linked to the development of diabetes, obesity, and fatty liver disease later in life with sex-specific manifestations. Alterations in miRNA expression in offspring exposed to GDM and maternal obesity and effects on hepatic development are unknown. Here, we describe how exposure to maternal obesity in utero leads to sex-specific changes in miRNA and target gene expression in human fetal liver. METHODS Candidate miRNA expression was measured in second trimester amniotic fluid (AF) from women with GDM. Targets of differentially expressed miRNAs were determined and pathway enrichment of target genes was performed. MiRNA and target gene expression were measured in a separate cohort of second trimester primary human fetal hepatocytes (PHFH) exposed to maternal obesity via qPCR and western blot. All studies were IRB approved. RESULTS GDM-exposed AF had significant increases in miRNAs 199a-3p, 503-5p, and 1268a (fold change (FC) ≥ 1.5, p < 0.05). Female offspring-specific analysis showed enrichment in miRNAs 378a-3p, 885-5p, and 7-1-3p (p < 0.05). MiRNA gene targets were enriched in hepatic pathways. Key genes regulating de novo lipogenesis were upregulated in obesity-exposed PHFH, especially in males. Significantly altered miRNAs in GDM AF were measured in obese-exposed PHFH, with consistent increases in miRNAs 885-5p, 199-3p, 503-5p, 1268a, and 7-1-3p (FC ≥ 1.5, p < 0.05). Female PHFH exposed to maternal obesity had increased expression of miR-885-5p, miR-199-3p, miR-503-5p, miR-1268s, and miR-7-1-3p (p < 0.05), corresponding to decreased target genes expression for ABCA1, PAK4, and INSR. In male PHFHs, no miRNA changes were measured but there was increased expression of ABCA1, PAK4, and INSR (p < 0.05). CONCLUSIONS Our data suggest sex-specific changes in miRNA and gene expression in PHFH may be one mechanism contributing to the sexual dimorphism of metabolic disease in offspring exposed to GDM and maternal obesity in utero.

中文翻译：

妊娠糖尿病和母体肥胖与胎儿中 miRNA 和靶基因表达的性别特异性变化有关。

背景/目的妊娠合并妊娠糖尿病 (GDM) 或母亲肥胖已与晚年糖尿病、肥胖和脂肪肝疾病的发展有关，并具有性别特异性表现。暴露于 GDM 和母亲肥胖的后代中 miRNA 表达的改变以及对肝脏发育的影响尚不清楚。在这里，我们描述了在子宫内暴露于母体肥胖如何导致人胎肝中 miRNA 和靶基因表达的性别特异性变化。方法在妊娠中期妊娠期羊水 (AF) 中测量了 GDM 女性的候选 miRNA 表达。确定差异表达的miRNA的靶标并进行靶基因的通路富集。通过 qPCR 和蛋白质印迹，在暴露于母体肥胖的孕中期原代人类胎儿肝细胞 (PHFH) 的单独队列中测量了 MiRNA 和靶基因表达。所有研究均获得 IRB 批准。结果暴露于 GDM 的 AF 的 miRNA 199a-3p、503-5p 和 1268a 显着增加（倍数变化 (FC) ≥ 1.5，p < 0.05）。雌性后代特异性分析显示 miRNA 378a-3p、885-5p 和 7-1-3p 富集（p < 0.05）。miRNA 基因靶点在肝脏通路中富集。在肥胖暴露的 PHFH 中，调节从头脂肪生成的关键基因上调，尤其是在男性中。在肥胖暴露的 PHFH 中测量到 GDM AF 中显着改变的 miRNA，miRNA 885-5p、199-3p、503-5p、1268a 和 7-1-3p 一致增加（FC ≥ 1.5，p < 0.05）。暴露于母体肥胖的女性 PHFH 的 miR-885-5p、miR-199-3p、miR-503-5p、miR-1268s 和 miR-7-1-3p 表达增加（p < 0.05），对应于降低的目标ABCA1、PAK4 和 INSR 的基因表达。在男性 PHFH 中，未测量到 miRNA 变化，但 ABCA1、PAK4 和 INSR 的表达增加（p < 0.05）。结论我们的数据表明，PHFH 中 miRNA 和基因表达的性别特异性变化可能是导致暴露于 GDM 和母体在子宫内肥胖的后代代谢疾病性别二态性的一种机制。

更新日期：2019-12-19

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