A poly-omic study of the molecular mechanisms underlying maternal diet interventions for offspring obesity and NAFLD
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Project SummaryThe demographic shift of populations toward a more obese phenotype in just one or two generationsappears to be primarily attributed to environmental or epigenetic mechanisms. Recent researchadvancements have highlighted the importance of nutrition during fetal and early life development andthus suggest an emerging need to evaluate the impact and risks of maternal diet schemes and understandthe molecular mechanism. Our recent published work reported in a murine model that switching from ahigh-fat (HF) diet to a normal-fat (NF) diet 1 week before pregnancy (H1N group) and maintained NFdiet until weaning, was not necessarily beneficial but actually exacerbates the offspring obesity andglucose intolerance, versus the offspring from the dam on a consistent maternal HF diet (HF group) or NFdiet (NF group) through weaning. In our follow up study, we evaluated the impacts of different durationsof 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 transitionduration led to less severe phenotype of obesity and non-alcoholic fatty liver disease (NAFLD). Ourtranscriptome data and gene ontology (GO) analysis identified significant association of differentmaternal diet-switch regimens with biological process involving lipid metabolism, energy utilization,epigenetic regulation and one-carbon pool metabolism and one-carbon transfer. Specifically, the DNAmethylation enzymes and the one-carbon pool by folate signaling for methionine cycle was suggested tobe affected by different maternal diet transition regimens. We hypothesize that maternal HF diet and ashort-term transition from a HF to a NF diet genetically upregulate the hepatic lipid profile throughinhibition of DNA methylation associated with disrupted methionine cycle; and a longer term transitionallows restoration of the methionine cycle. To test this hypothesis, we propose to determine that hepaticlipid profiles are genetically regulated by different maternal diet transition regimens by lipidomics andsignaling pathway analysis on lipid metabolism (Aim1). We will determine that global DNA methylationwas differentially altered by different maternal diet transition regimens which lead to differentialexpression of genes involved in lipid metabolism in liver by bisulfite sequencing and an integrativeanalysis for identifying lipid metabolism specific DNA methylation by different maternal dietinterventions (Aim2). Lastly, we will determine that disrupted methionine cycle caused by maternal HFdiet contributes to offspring obesity and NAFLD, which is reversed by a long-term, but not a short-termtransition from a HF to a NF diet (Aim3). This proposed study will potentially fill the gap in the fieldbetween lipid metabolism and epigenetics in transgeneration and therefore understand how maternal dietinterventions would affect offspring health status.