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 人口的人口转变仅一代或两代人的肥胖表型 似乎主要归因于环境或表观遗传机制。最近的研究 进步强调了营养在胎儿和早期生命发展期间的重要性 因此，提出了新兴的需求，以评估孕产妇饮食方案的影响和风险并了解 分子机制。我们最近发表的工作在鼠模型中报道了 怀孕前1周（H1N组）高脂（HF）饮食至正常脂肪（NF）饮食并保持NF 饮食直到断奶，不一定是有益的，但实际上会加剧后代肥胖和 葡萄糖不耐症，与一致的母体HF饮食（HF组）或NF的大坝后代相比 饮食（NF组）通过断奶。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饮食的母体饮食过渡，即1周（H1N组），5周（H5N组） 或在怀孕前的9周（H9N组），后代肥胖。我们发现更长的过渡 持续时间导致肥胖和非酒精性脂肪肝病（NAFLD）的严重表型。我们的 转录组数据和基因本体论（GO）分析确定了不同的不同关联 孕产妇开关方案具有涉及脂质代谢，能量利用的生物学过程， 表观遗传调节和一碳池的代谢和一碳转移。具体而言，DNA 甲基化酶和通过叶酸信号传导的甲二氨酸循环的甲基化酶被提示为 受孕产妇饮食过渡方案的影响。我们假设母体HF饮食和A 从HF到NF饮食的短期过渡通过基因上调肝脂质谱。 抑制与破坏蛋氨酸循环有关的DNA甲基化；和长期过渡 允许恢复蛋氨酸周期。为了检验这一假设，我们建议确定肝 脂质谱受脂肪组学和不同母体饮食过渡方案的遗传调节 脂质代谢的信号通路分析（AIM1）。我们将确定全局DNA甲基化 通过不同的母体饮食过渡方案差异改变，这导致差异 甲硫酸氢盐测序和综合性的肝脏中脂质代谢的基因表达 分析通过不同母体饮食来鉴定脂质代谢特异性DNA甲基化 干预措施（AIM2）。最后，我们将确定由母体HF引起的蛋氨酸周期破坏 饮食有助于后代肥胖和NAFLD，这是长期的，但不是短期的 从HF过渡到NF饮食（AIM3）。这项拟议的研究可能会填补现场的空白 脂质代谢和转化的表观遗传学之间，因此了解孕产妇饮食如何 干预将影响后代健康状况。