A poly-omic study of the molecular mechanisms underlying maternal diet interventions for offspring obesity and NAFLD

母亲饮食干预对后代肥胖和 NAFLD 分子机制的多组学研究

• 批准号: 9903288
• 负责人: LingLin Xie
• 金额: $ 47.14万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903288
• 关键词: Adult; Adverse effects; Affect; Amino Acids; Betaine; Biological Markers; Biological Process; Candidate Disease Gene; Carbon; Child; Cholesterol Esters; Choline; DNA Methylation; DNA Methylation Inhibition; DNA Sequence Alteration; Data; Development; Diet; Dietary Intervention; Down-Regulation; Enzymes; Epigenetic Process; FRAP1 gene; Fatty acid glycerol esters; Folic Acid; Follow-Up Studies; Gene Expression; Generations; Genes; Genetic; Glucose Intolerance; Growth; Health; Health Status; Healthcare; Hepatic; High Fat Diet; Homeostasis; Homocysteine; Human; Intervention; Knowledge; Lead; Life; Lipids; Liver; Measures; Messenger RNA; Metabolic syndrome; Metabolism; Methionine; Methylation; Mission; Molecular; Mothers; Mus; Nonesterified Fatty Acids; Obesity; Obesity associated disease; One Carbon Pool by Folate Pathway; Ontology; Outcome; Pathway Analysis; Peroxisome Proliferator-Activated Receptors; Phenotype; Policies; Population; Pregnancy; Public Health; Publishing; Regimen; Regulatory Pathway; Reporting; Research; Resources; Reverse Transcriptase Polymerase Chain Reaction; Risk Reduction; Scheme; Signal Pathway; Signal Transduction; Site; Supplementation; Testing; Tissue-Specific Gene Expression; Triglycerides; United States National Institutes of Health; Variant; Vitamin B 12; Weaning; Work; adverse event risk; base; bisulfite; bisulfite sequencing; differential expression; epigenetic regulation; experimental study; fetal; gene repression; insight; lipid metabolism; maternal risk; mother nutrition; mouse model; non-alcoholic fatty liver disease; nutrition; obesity prevention; offspring; offspring obesity; restoration; transcriptome; whole genome

Project Summary The demographic shift of populations toward a more obese phenotype in just one or two generations appears to be primarily attributed to environmental or epigenetic mechanisms. Recent research advancements have highlighted the importance of nutrition during fetal and early life development and thus suggest an emerging need to evaluate the impact and risks of maternal diet schemes and understand the molecular mechanism. Our recent published work reported in a murine model that switching from a high-fat (HF) diet to a normal-fat (NF) diet 1 week before pregnancy (H1N group) and maintained NF diet until weaning, was not necessarily beneficial but actually exacerbates the offspring obesity and glucose intolerance, versus the offspring from the dam on a consistent maternal HF diet (HF group) or NF diet (NF group) through weaning. In our follow up study, we evaluated the impacts of different durations of maternal diet transition from a HF to a NF diet, which was 1 week (H1N group), 5 weeks (H5N group) or 9 weeks (H9N group), before pregnancy, on offspring obesity. We found that a longer transition duration led to less severe phenotype of obesity and non-alcoholic fatty liver disease (NAFLD). Our transcriptome data and gene ontology (GO) analysis identified significant association of different maternal diet-switch regimens with biological process involving lipid metabolism, energy utilization, epigenetic regulation and one-carbon pool metabolism and one-carbon transfer. Specifically, the DNA methylation enzymes and the one-carbon pool by folate signaling for methionine cycle was suggested to be affected by different maternal diet transition regimens. We hypothesize that maternal HF diet and a short-term transition from a HF to a NF diet genetically upregulate the hepatic lipid profile through inhibition of DNA methylation associated with disrupted methionine cycle; and a longer term transition allows restoration of the methionine cycle. To test this hypothesis, we propose to determine that hepatic lipid profiles are genetically regulated by different maternal diet transition regimens by lipidomics and signaling pathway analysis on lipid metabolism (Aim1). We will determine that global DNA methylation was differentially altered by different maternal diet transition regimens which lead to differential expression of genes involved in lipid metabolism in liver by bisulfite sequencing and an integrative analysis for identifying lipid metabolism specific DNA methylation by different maternal diet interventions (Aim2). Lastly, we will determine that disrupted methionine cycle caused by maternal HF diet contributes to offspring obesity and NAFLD, which is reversed by a long-term, but not a short-term transition from a HF to a NF diet (Aim3). This proposed study will potentially fill the gap in the field between lipid metabolism and epigenetics in transgeneration and therefore understand how maternal diet interventions would affect offspring health status.

项目摘要 人口在一两代人中向更肥胖表型的人口转变 似乎主要归因于环境或表观遗传机制。最近的研究 这些进展突出了营养在胎儿和生命早期发育期间的重要性， 因此，建议有必要评估产妇饮食计划的影响和风险，并了解 分子机制。我们最近发表的工作报告在一个小鼠模型中，从一个 妊娠前1周（H1 N组）高脂（HF）饮食改为正常脂肪（NF）饮食，并维持NF 断奶前的饮食不一定有益，但实际上会加剧后代的肥胖， 葡萄糖不耐受，与来自母亲的后代一致的HF饮食（HF组）或NF 日粮（NF组）。在我们的后续研究中，我们评估了不同持续时间的影响 从HF到NF的过渡时间分别为1周（H1 N组）、5周（H5 N组） 或孕9周（H9 N组）对子代肥胖的影响。我们发现， 持续时间导致肥胖和非酒精性脂肪性肝病（NAFLD）的严重表型较轻。我们 转录组数据和基因本体论（GO）分析确定了不同的 母体饮食转换方案具有涉及脂质代谢、能量利用 表观遗传调控和一碳库代谢及一碳转移。具体来说，DNA 甲基化酶和一个碳库的叶酸信号蛋氨酸循环，建议 受不同的母亲饮食过渡方案的影响。我们假设母亲的HF饮食和 从HF到NF饮食的短期过渡在遗传上上调了肝脏脂质谱， 与破坏的甲硫氨酸循环相关的DNA甲基化抑制;以及更长期的过渡 使蛋氨酸循环得以恢复。为了验证这一假设，我们建议确定肝脏 脂质组学通过不同的母体饮食过渡方案对脂质谱进行遗传调节， 脂质代谢信号通路分析（Aim 1）。我们将确定全球DNA甲基化 不同的母亲饮食过渡方案，导致不同的 通过亚硫酸氢盐测序和整合技术研究肝脏脂质代谢相关基因的表达 不同母亲饮食对脂代谢特异性DNA甲基化的影响 （目标2）。最后，我们将确定母体HF引起的蛋氨酸循环中断 饮食有助于后代肥胖和NAFLD，这是逆转的长期，但不是短期的。 从HF到NF饮食的过渡（Aim 3）。这项拟议的研究将有可能填补该领域的差距 脂质代谢和表观遗传学之间的联系，从而了解母亲的饮食 干预措施会影响后代的健康状况。