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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要仅仅一两代人的人口结构就向更肥胖的表型转变似乎主要归因于环境或表观遗传机制。最近的研究进步凸显了营养在胎儿和早期生命发育过程中的重要性，因此，迫切需要评估孕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小鼠模型中从怀孕前 1 周从高脂肪 (HF) 饮食改为正常脂肪 (NF) 饮食（H1N 组）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症，与持续母体 HF 饮食（HF 组）或 NF 的母鼠的后代相比通过断奶饮食（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母亲饮食从 HF 饮食转变为 NF 饮食的时间，分别为 1 周（H1N 组）、5 周（H5N 组）或 9 周（H9N 组），怀孕前，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（NAFLD）的严重表型减轻。我们的转录组数据和基因本体（GO）分析确定了不同基因之间的显着关联母亲饮食转换方案涉及脂质代谢、能量利用、表观遗传调控和一碳库代谢和一碳转移。具体来说，DNA 建议通过叶酸信号转导蛋氨酸循环的甲基化酶和一碳池受到不同母亲饮食转变方案的影响。我们假设母亲 HF 饮食和从 HF 饮食到 NF 饮食的短期过渡会通过基因上调肝脏脂质分布抑制与蛋氨酸循环中断相关的 DNA 甲基化；以及更长期的过渡允许恢复蛋氨酸循环。为了检验这一假设，我们建议确定肝脏通过脂质组学和研究，血脂谱受到不同母亲饮食转变方案的遗传调节脂质代谢信号通路分析（Aim1）。我们将确定全球 DNA 甲基化不同的母亲饮食转变方案有不同的改变，从而导致不同的通过亚硫酸氢盐测序和综合分析肝脏脂质代谢相关基因的表达分析不同母亲饮食对脂质代谢特异性 DNA 甲基化的影响干预措施（目标 2）。最后，我们将确定母体心衰引起的蛋氨酸循环中断饮食会导致后代肥胖和 NAFLD，这种情况可以通过长期而不是短期的逆转来逆转从 HF 饮食过渡到 NF 饮食（目标 3）。这项拟议的研究将有可能填补该领域的空白转基因中脂质代谢和表观遗传学之间的关系，从而了解母亲饮食如何干预措施会影响后代的健康状况。