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

孕前减肥引起的母亲代谢和分子变化及其对出生结局的影响

• 批准号: 10267204
• 负责人: CHARLES F BURANT
• 金额: $ 59.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10267204
• 关键词: Adult; Affect; Air; Amino Acids; Birth; Birth Weight; Blood; Body Composition; Body Weight decreased; Body mass index; Cardiometabolic Disease; Child; Childhood; Chromatin Structure; Chronic Disease; Clinical; Collection; Computer Models; Conceptions; Confounding Factors (Epidemiology); Counseling; Cross-Sectional Studies; DNA Methylation; Development; Diabetes Mellitus; Diet; Disease; Environment; Environmental Exposure; Epigenetic Process; Exposure to; Factor Analysis; Fetal Development; Fetal Growth; First Pregnancy Trimester; Gene Expression; Genes; Genetic; Genome; Gestational Diabetes; Health; Heart Diseases; High birth weight infant; Human; Hybrids; Hypertension; Infant; Inflammation; Inflammatory; Institutional Review Boards; Intervention; Leukocytes; Lipids; Literature; Lymphocyte; Maternal complication; Measures; Mediating; Medical; Messenger RNA; Metabolic; Metabolism; Methylation; Michigan; Modeling; Molecular; Molecular Profiling; Mothers; Multivariate Analysis; Neonatal; Newborn Infant; Non obese; Nutrient; Nutritional; Obesity; Observational Study; Outcome; Overweight; Pathway interactions; Phenotype; Physiological; Pisum sativum; Plasma; Plethysmography; Pregnancy; Pregnancy Complications; Pregnant Women; Proteome; Proteomics; Randomized; Regression Analysis; Resources; Risk; Risk Marker; Rodent; Sampling; Second Pregnancy Trimester; Testing; Thinness; Ultrasonography; Umbilical Cord Blood; Universities; Weight; Woman; Women' s Group; cardiometabolic risk; clinical phenotype; design; epigenome; epigenomics; experience; fetal; fetal adiposity; gestational weight gain; histone modification; improved; in utero; indexing; infant outcome; inflammatory marker; intrauterine environment; lipidomics; maternal obesity; maternal outcome; metabolome; metabolomics; methylation pattern; methylome; molecular phenotype; neonate; nutrition; obese mothers; obesity in children; obesity risk; offspring; prepregnancy; programs; prospective; recruit; response; standard of care; success; transcriptome sequencing; weight loss intervention

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.

抽象的 怀孕期间的孕产妇肥胖会增加高血压，妊娠糖尿病和异常的风险 胎儿生长，婴儿早期和晚期的婴儿出生体重和BMI较高。广泛的文献提供 发育中的胎儿表观遗传编程的证据，以应对母体代谢环境，但 有最少的直接证据表明胎儿环境的变化可以改变表观基因组。提议 研究将检验以下假设，即在概念之前进行重大减肥将改善内部代谢 环境反映在母体代谢组和注射相关蛋白质组中，并导致变化 在脐带血白细胞中的甲基化模式中。为了检验这一假设，提出了三个具体目标。目的 1，将检查300名肥胖女性的代谢内部环境（BMI> 30 kg/m2≤45kg/m2） 将随机分配到靶向> 15％体重减轻或标准的非常低的能量饮食（VLED） 护理（SOC）干预措施。以及120名精益女性（精益）作为比较者，VLED和SOC妇女 将经历广泛的孕前临床和物理表型和血液收集。肥胖的妇女 体重减轻后将进行额外的表型，所有妇女将在每个三个月进行额外的测试。 我们希望每组中有87个后代。胎儿生长将通过超声和​​后代的出生体重评估 （Ponderal指数），肥胖（Pea Pod Air置换术）。在AIM 2中，血浆代谢组学和 （杂种靶向/不靶向和脂质组学）和炎症标记将用于评估干预措施 相关的VLED和SOC妇女的变化，并与Vled妇女进行了比较。评估插科 环境，代谢组谱和炎症蛋白质组将在头三个月和期间测量 在所有母亲和胎儿血液中。多元计算模型将评估母体的关联 以及新生儿代谢组和炎症标志物，胎儿生长以及新生儿体重和肥胖。目标 3，将从所有后代的胎儿血液淋巴细胞中获得DNA甲基化模式和RNA-seq。 VLED，SOC和瘦肉之间的甲基化模式差异将评估和mRNA的变化 将确定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以及胎儿生长和出生结果有关。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甲基化有关，并研究是否是否 胎儿的生长或出生体重和其他结果是由特定代谢产物介导的。这些研究的结果 将首先评估对内胎的先入观念体重减轻的好处 新生儿的环境和分子变化，并将提供孕产妇的潜在途径 内部环境以及后代体重和代谢状态的编程变化。