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、妊娠期糖尿病和异常的风险 婴儿出生体重和BMI在儿童早期和晚期的胎儿生长发育。广泛的文献提供了 有证据表明，发育中的胎儿对母体代谢环境做出了表观遗传规划，但是 很少有直接证据表明胎儿环境的变化会改变表观基因组。建议数 研究将检验这一假设，即怀孕前显著减肥将改善宫内代谢。 反映在母体代谢组和炎症相关蛋白质组中的环境并导致变化 脐带血白细胞的甲基化模式。为了验证这一假设，本文提出了三个具体目标。目标 1，将检查300名肥胖女性(BMI和GT；30 kg/m2≤45 kg/m2)的宫内代谢环境。 将随机分为非常低能量饮食(VLED)，目标是体重减轻15%或标准 护理(SOC)干预。以及120名瘦身女性(Lean)作为参照者，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 在减肥后将接受额外的表型鉴定，所有女性在每三个月都将接受额外的测试。 我们预计每组有87只后代。胎儿发育将通过超声波和后代出生体重进行评估。 (体重指数)、肥胖症(豌豆荚空气置换描记)。在目标2中，血浆代谢组学和 (混合靶向/非靶向和脂质组学)和炎症标记物将用于评估干预 VLED和SOC女性的相关变化，并与VLED女性进行比较。以评估宫内情况 环境、代谢组谱和炎性蛋白质组将在妊娠的前三个月和足月进行测量 在所有母亲和胎儿脐带血中。多变量计算模型将评估母体之间的关联 以及新生儿代谢组和炎性标志物对胎儿生长、新生儿体重和肥胖的影响。在AIM 3、从所有子代的胎儿脐血淋巴细胞中获得DNA甲基化模式和RNA-SEQ。 将评估VLED、SOC和LEAN之间甲基化模式的差异以及mRNA的变化 将确定甲基化水平以评估甲基化对基因表达的影响。多变量分析 甲基化模式将与代谢组相关，并与胎儿生长和出生结局有关。使用稀疏 多元因素分析回归模型(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，并调查 胎儿生长或出生体重和其他结果是由特定代谢物调节的。这些研究的结果 将首次对先入为主的减肥对宫内的益处进行前瞻性评估 新生儿的环境和分子变化，并将提供一条潜在的途径，从母亲 宫内环境与子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.