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 母亲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 大量文献提供了儿童早期和晚期婴儿出生体重和体重指数较高的胎儿生长情况。 发育中的胎儿的表观遗传编程响应母体代谢环境的证据，但是 几乎没有直接证据表明胎儿环境的变化可以改变表观基因组。 研究将检验以下假设：受孕前显着减轻体重会改善子宫内代谢 母体代谢组和炎症相关蛋白质组反映的环境并导致变化 为了检验这一假设，提出了三个具体目标。 1、将检查300名肥胖女性（BMI>30 kg/m2≤45 kg/m2）的宫内代谢环境 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 护理 (SOC) 干预措施与 120 名瘦女性 (LEAN) 一起作为比较者、VLED 和 SOC 女性。 将接受广泛的孕前临床和生理表型分析以及肥胖女性的血液采集。 减肥后将接受额外的表型分析，所有女性将在每个三个月进行额外的测试。 我们预计每组 87 名后代将通过超声波和后代出生体重进行评估。 （体重指数）、肥胖（目标 2 中的豌豆荚空气置换体积描记法）、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措施 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。 将在妊娠早期和足月测量环境、代谢组学特征和炎症蛋白质组 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。 新生儿代谢组和炎症标志物对胎儿生长、新生儿体重和肥胖的影响。 3、从所有后代的胎儿脐带血淋巴细胞中获得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 将确定水平以评估甲基化对基因表达的影响。 甲基化模式与代谢组以及胎儿生长和出生结果有关。 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，并研究是否 胎儿生长或出生体重和其他结果是由特定代谢物介导的。 将首次对孕前减肥对宫内胎儿的益处进行前瞻性评估 新生儿的环境和分子变化将为母体提供潜在的途径 子宫内环境以及后代体重和代谢状态的程序性变化。