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

项目摘要 人口在一到两代人中向更肥胖表型的转变 似乎主要归因于环境或表观遗传机制。最新研究 研究进展突显了营养在胎儿和早期生命发育中的重要性 因此，有必要评估母亲饮食计划的影响和风险，并了解 分子机制。我们最近发表的研究报告说，在一个小鼠模型中，从一个 孕前1周高脂(HF)饮食至正常脂肪(NF)饮食(H1N组)和维持正常脂肪(NF)饮食 断奶前的饮食，并不一定有益，但实际上会加剧后代的肥胖和 糖耐量异常，与母亲一致的HF饮食(HF组)或核因子的母体后代的比较 断奶饲料组(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) 或孕前9周(H9N组)，观察子代肥胖情况。我们发现，更长的过渡期 持续时间导致肥胖和非酒精性脂肪性肝病(NAFLD)的表型不那么严重。我们的 转录组数据和基因本体论(GO)分析发现不同的 通过生物过程改变母亲饮食，包括脂肪代谢，能量利用， 表观遗传调控与一碳池代谢和一碳转移。具体来说，DNA 甲基化酶和通过叶酸信号转导蛋氨酸循环的单碳库被认为是 会受到不同的母亲饮食转变方案的影响。我们假设母亲的HF饮食和一个 从HF饮食到NF饮食的短期转变通过以下方式从基因上上调肝脏脂肪含量 与蛋氨酸循环中断相关的DNA甲基化抑制；以及更长时间的过渡 允许蛋氨酸循环的恢复。为了验证这一假设，我们建议确定肝脏 不同的母体饮食转变方案通过脂类组学和 脂代谢信号通路分析(Aim1)。我们将确定全球DNA甲基化 不同的母亲饮食转变方案会导致不同的改变 亚硫酸氢盐测序法和一体法研究肝脏脂代谢相关基因的表达 不同母体饮食对脂代谢特异性DNA甲基化的鉴定分析 干预措施(AIM2)。最后，我们将确定母体心衰引起的蛋氨酸循环紊乱 饮食有助于后代肥胖和NAFLD，这可以被长期的，但不是短期的逆转 从HF饮食过渡到NF饮食(Aim3)。这项拟议的研究可能会填补这一领域的空白。 在变性过程中脂代谢和表观遗传学之间的关系，从而理解母亲的饮食 干预措施会影响后代的健康状况。

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.