Maternal metabolic and molecular changes induced by preconception weight loss and their effects on birth outcomes

摘要 孕妇在怀孕期间肥胖会增加患高血压、妊娠期糖尿病和胎儿畸形的风险。 在儿童早期和晚期，胎儿生长与婴儿出生体重和BMI较高有关。大量文献提供了 发育中的胎儿对母体代谢环境做出反应的表观遗传编程的证据，但 只有极少的直接证据表明胎儿环境的变化可以改变表观基因组。拟议 研究将检验以下假设：受孕前显着减肥将改善宫内代谢 在母体代谢组和炎症相关蛋白质组中反映的环境变化， 在脐带血白细胞的甲基化模式中。为了验证这一假设，提出了三个具体目标。目的 1，将检查300名肥胖妇女（BMI>30 kg/m2 ≤ 45 kg/m2）的代谢宫内环境， 将被随机分配到以>15%体重减轻为目标的极低能量饮食（VLED）或标准的 护理（SOC）干预。沿着120名瘦女性（LEAN）作为对照，VLED和SOC女性 将接受广泛的孕前临床和生理表型分析和血液采集。肥胖女性 将在减肥后进行额外的表型分析，所有女性将在每三个月进行额外的测试。 我们预计每组有87个后代。胎儿生长将通过超声和后代出生体重进行评估 （重量指数），肥胖（豌豆荚空气置换体积描记法）。在目标2中，血浆代谢组学和 （混合靶向/非靶向和脂质组学）和炎症标志物将用于评估干预 VLED和SOC女性的相关变化，并与VLED女性进行比较。评估子宫内 环境，代谢组学和炎症蛋白质组将在妊娠早期和足月时进行测量 在所有母亲和胎儿脐带血中。多变量计算模型将评估孕产妇死亡率与死亡率之间的关系。 以及新生儿代谢组和炎症标记物对胎儿生长和新生儿体重和肥胖的影响。在Aim中 3、DNA甲基化模式和RNA-seq将从所有后代的胎儿脐带血淋巴细胞获得。 将评估VLED、SOC和LEAN之间甲基化模式的差异，并将评估VLED、SOC和LEAN之间mRNA水平的变化。 将测定甲基化水平以评估甲基化对基因表达的影响。的多因素分析 甲基化模式将与代谢组以及胎儿生长和出生结果相关。使用稀疏 多元因子分析回归模型（smFARM）和其他统计方法，我们将确定如何 母体代谢组和蛋白质组与脐带血DNA甲基化相关， 胎儿生长或出生体重和其他结果是由特定的代谢物介导的。这些研究的结果 将提供第一个前瞻性评估孕前体重减轻对子宫内胎儿的益处， 新生儿的环境和分子变化，并将提供一个潜在的途径， 宫内环境和后代体重和代谢状态的程序性变化。

Abstract Maternal obesity during pregnancy increases the risk of hypertension, gestational diabetes and abnormalities in fetal growth with higher infant birth weight and BMI in both early and late childhood. Extensive literature provides evidence for epigenetic programming of the developing fetus in response to the maternal metabolic milieu, but there is minimal direct evidence that changes in the fetal environment can alter the epigenome. The proposed study will test the hypothesis that significant weight loss prior to conception will improve the intrauterine metabolic environment as reflected in the maternal metabolome and inflammation-related proteome and result in changes in methylation patterns in cord blood leukocytes. To test this hypothesis, three Specific Aims are proposed. Aim 1, will examine the metabolic intrauterine environment in 300 obese women (BMI>30 kg/m2 ≤ 45 kg/m2) who will be randomized to either Very Low Energy Diet (VLED) targeting a >15% body weight loss or Standard of Care (SOC) interventions. Along with 120 lean women (LEAN) serving as comparators, VLED and SOC women will undergo extensive prepregnancy clinical and physiological phenotyping and blood collections. Obese women will undergo additional phenotyping after weight loss and all women will have additional testing at each trimester. We expect 87 offspring in each group. Fetal growth will be assessed by ultrasound and offspring birth weight (Ponderal index), adiposity (Pea Pod Air Displacement Plethysmography). In Aim 2, plasma metabolomics and (hybrid targeted/untargeted and lipidomics) and inflammatory markers will be used to assess intervention associated changes in VLED and SOC women and compared to VLED women. To assess the intrauterine environment, metabolomic profiles and inflammatory proteome will be measured in the first trimester and at term in all mothers and in fetal cord blood. Multivariate computational models will assess the association of maternal and neonate metabolome and inflammatory markers to fetal growth and newborn weight and adiposity. In Aim 3, DNA methylation patterns and RNA-seq will be obtained from fetal cord blood lymphocytes of all offspring. Differences in methylation patterns between VLED, SOC and LEAN will be assessed and changes in mRNA levels will be determined to assess the effect of methylation on gene expression. Multivariate analysis of methylation patterns will be related to the metabolome and to fetal growth and birth outcomes. Using sparse multivariate factor analysis regression model (smFARM) and other statistical approaches, we will determine how the maternal metabolome and proteome is associated with cord blood DNA methylation and investigate whether fetal growth or birth weight and other outcomes are mediated by specific metabolites. The results of these studies will provide the first prospective assessment of the benefit of preconception weight loss on the intrauterine environment and molecular changes in the newborn and will provide a potential pathway from maternal intrauterine environment and programmed changes in weight and metabolic status in offspring.