Administrative Supplement to Placental miRNA profiles associated with maternal insulin resistance and fetal adiposity: maternal-placental crosstalk

项目摘要 出生时高肥胖与儿童时期代谢结果差和肥胖风险增加有关 和成年人的生活。母亲肥胖(体重指数和30公斤/平方米)与胎儿肥胖症增加有关，但 并不是所有肥胖的女性都有肥胖的婴儿。非西班牙裔黑人或非裔美国女性经历 不成比例的孕前肥胖和胎儿生长受限，以及其他贫穷 妊娠结局--然而，在调查以下因素的影响的围产期研究中，这一比例偏低 母体代谢对胎儿生长发育的影响。母亲对胰岛素的敏感性是胎儿脂肪增加的关键预测因素，但 在怀孕期间调节胰岛素信号的机制尚不清楚。我们发现母体胰岛素 胎盘植入后敏感度提高120%，提示胎盘因素可能调节胰岛素 在怀孕期间发出信号。由于胎盘生长和基因表达对母体胰岛素水平敏感 ，并与出生时肥胖有关，我们认为母体-胎盘串扰是 胎儿生长调节。胎盘来源的microRNAs(MiRNA)调节胚胎发育过程中转录后基因表达 母体组织，并在整个怀孕期间在母体血浆中检测到。因此，miRNAs可以提供 这既是母体-胎盘串扰的机制，也是高胎儿脂肪风险女性的新指标 吸积作用。本附录的总体目标是利用一个表型良好、种族多样的出生队列来 识别与母体胰岛素抵抗改变相关的胎盘miRNA表达谱 在整个怀孕期间，会导致新生儿高度肥胖。我们假设高肥胖症的胎盘 婴儿有一个独特的miRNA表达谱，影响母体胰岛素信号，导致高 母体胰岛素抵抗。为了验证这一假设，我们将使用从出生队列中预先收集的样本。 该队列由四组组成：生育高或低脂肪后代的瘦身和肥胖女性。 这些妇女都有健康的妊娠，没有糖尿病，并在预定的剖腹产时招募。 采集母体血液、胰岛素敏感性数据和胎盘组织的部分，以及新生儿 测量肥胖程度。这项补充研究将确定胎盘miRNA在 这四个肥胖症群体受到母亲种族/民族的影响，因为胎儿生长和身体的种族差异 其组成已有报道。在完成建议的研究后，我们会决定：1) 瘦型和肥胖型胎盘中与新生儿高肥胖症相关的miRNAs识别 非西班牙裔黑人和白人妇女；2)这些miRNA循环水平之间的关系 母体对足月胰岛素的敏感性。影响胎盘功能改变的标志物的鉴定 在怀孕期间可以无创检测到的新生儿肥胖症将改善我们对高危妊娠的筛查 可能导致胎儿脂肪过度堆积，并可能导致基于潜在生理学的特定治疗。

Project Abstract High adiposity at birth is associated with poor metabolic outcomes and increased risk of obesity in childhood and adult life. Maternal obesity (body mass index >30 kg/m2) is associated with increased fetal adiposity, but not all obese women have obese babies. Non-Hispanic Black or African American women experience a disproportionate amount of pre-pregnancy obesity and fetal growth restriction, in addition to other poor pregnancy outcomes – yet are underrepresented in perinatal research studies investigating the effects of maternal metabolism on fetal growth. Maternal insulin sensitivity is a key predictor of fetal fat accrual, but the mechanisms regulating insulin signaling during pregnancy are unknown. We have found that maternal insulin sensitivity improves 120% following delivery of the placenta, suggesting a placental factor may regulate insulin signaling during pregnancy. As placental growth and gene expression is sensitive to maternal insulin levels in early pregnancy, and correlated to adiposity at birth, we propose that maternal-placental crosstalk is key to fetal growth regulation. Placental-derived microRNAs (miRNA) regulate post-transcriptional gene expression in maternal tissues, and are detectable in maternal plasma throughout pregnancy. Thus, miRNAs may provide both a mechanism for maternal-placental crosstalk, and novel indicators of women at risk of high fetal fat accretion. The overall goal of this supplement is to utilize a well-phenotyped, racially-diverse birth cohort to identify placental miRNA expression profiles associated with alterations in maternal insulin resistance throughout pregnancy resulting in high neonatal adiposity. We hypothesize that placentas of high adiposity infants have a distinctive miRNA expression profile affecting maternal insulin signaling, resulting in high maternal insulin resistance. To test this hypothesis, we will utilize pre-collected samples from our birth cohort. The cohort consists of four groups: lean and obese women who delivered high or low adiposity offspring. These women all had healthy pregnancies, were not diabetic, and recruited at time of scheduled cesarean section where maternal blood, insulin sensitivity data and placental tissue were collected, and neonatal adiposity was measured. This supplemental study will determine whether placental miRNA expression within these four adiposity groups is affected by maternal race/ethnicity, as racial disparities in fetal growth and body composition have been reported. Upon completion of the proposed studies we will have determined: 1) the identity of miRNAs that are associated with high neonatal adiposity in placentas of lean and obese non-Hispanic Black and White women; 2) the relationship between circulating levels of these miRNA and maternal insulin sensitivity at term. Identification of markers of altered placental function affecting neonatal adiposity, detectable non-invasively in pregnancy, will improve our screening for pregnancies at risk of excessive fetal fat accretion and may lead to specific therapies based on the underlying physiology.