Abstract：
The increasing prevalence of obesity, type 2 diabetes mellitus (T2DM), and gestational diabetes (GDM) among pregnant women has risen dramatically worldwide. The antihyperglycemic drug metformin is the most common drug for T2DM treatment in non-pregnant individuals; nevertheless, it is increasingly being used for diabetes-complicated pregnancies. Studies on the long-term metabolic effects of this drug in offspring remain scarce. This work aimed to determine the effect of metformin exposure during pregnancy and lactation on the offspring of a model of diet-induced maternal hyperglycemia. Cohorts of pregnant mice were fed a 46% fat diet (HFD) or a control standard diet (SD). A group of dams were exposed to metformin during pregnancy and lactation. After weaning, the offspring were fed SD for 8 weeks and then challenged with a 46% HFD after puberty for 12 weeks. Irrespective of the maternal diet, offspring of metformin-exposed mothers had a lower body weight and reduced inguinal white adipose tissue (iWAT) mass after HFD challenge. This was associated with increased expression of Pparg, Fabp4, Glut4, Srebp1, and Fasn in the iWAT during adulthood in the metabolically impaired dams exposed to metformin, suggesting increased adipogenesis and de novo lipogenesis. Increased expression of Fasn associated with decreased methylation levels at its promoter and proximal coding region in the iWAT was found. These results suggest that metformin modulates gene expression levels by epigenetic mechanisms in maternal metabolic-impaired conditions.
摘要：
肥胖的患病率越来越高，2型糖尿病（T2DM），妊娠糖尿病（GDM）在全球范围内急剧上升。抗高血糖药物二甲双胍是非妊娠个体治疗T2DM最常用的药物;然而,它越来越多地用于糖尿病并发的妊娠。关于这种药物对后代的长期代谢作用的研究仍然很少。这项工作旨在确定妊娠和哺乳期二甲双胍暴露对饮食诱导的母体高血糖模型后代的影响。向怀孕小鼠的组群饲喂46%脂肪饮食(HFD)或对照标准饮食(SD)。一组母羊在怀孕和哺乳期间暴露于二甲双胍。断奶后,给后代喂食SD8周，然后在青春期后用46％的HFD攻击12周。不管母亲的饮食，暴露于二甲双胍的母亲的后代在HFD攻击后体重较低,腹股沟白色脂肪组织(iWAT)质量减少。这与Pparg的表达增加有关，在暴露于二甲双胍的代谢受损水坝中，成年期iWAT中的Fabp4，Glut4，Srebp1和Fasn，提示脂肪生成和从头脂肪生成增加。发现Fasn的表达增加与iWAT中启动子和近端编码区的甲基化水平降低相关。这些结果表明，二甲双胍在母体代谢受损的条件下通过表观遗传机制调节基因表达水平。
