Maternal Western Diet Programs Cardiometabolic Dysfunction and Hypothalamic Inflammation via Epigenetic Mechanisms Predominantly in the Male Offspring [Methyl-seq]

Maternal exposure during pregnancy is a strong determinant of offspring health outcomes. Such exposures induce changes in the offspring epigenome resulting in gene expression and functional changes. In this study, we investigated the effect of maternal Western hypercaloric diet (HCD) programming during the perinatal period and its effect on neuronal plasticity and cardiometabolic health in adult offspring. C57BL/6J dams were fed HCD for 1 month prior to mating with regular diet (RD) sires and kept on the same diet throughout pregnancy and lactation. At weaning, offspring were maintained on either HCD or RD for 3 months duration. Maternal programming resulted in male-specific hypertension and hyperglycemia, with both males and females showing increased sympathetic tone to the vasculature. Surprisingly, programmed male offspring fed on HCD exhibited lower glucose levels, less insulin resistance, and leptin levels compared to non-programmed HCD-fed male mice. Hypothalamic genes involved in glial and astrocytic differentiation were differentially methylated in programmed male offspring. Genes involved in inflammation and type 2 diabetes were targeted by differentially expressed miRNA in programmed male offspring. Methyl-seq data were supported by our findings of astrogliosis and microgliosis as well as increased microglial activation in programmed males in the paraventricular nucleus (PVN). Aligned with programming-induced protective effect in HCD male mice, we observed lower protein levels of hypothalamic TGFß2, NF-?B2, NF-?Bp65, Ser-pIRS1, and GLP1R compared to non-programmed HCD-fed male mice. In conclusion, our study shows that maternal HCD programs neuronal plasticity in the offspring and results in male-specific hypertension and hyperglycemia. On the other hand, we observed a compensatory role of programming potentially by priming metabolic pathways to handle excess nutrients in a more efficient way. Overall design: These are methyl-seq data driven from the hypothalamus of programmed mice with perinatal hypercaloric diet and non-programmed mice with either postnatal HCD or regular diet. First part of the name refers to maternal diet and the second part refers to offspring diet.

妊娠期母体暴露状况是子代健康结局的重要决定因素。此类暴露会诱导子代表观基因组发生改变，进而引发基因表达与功能层面的变化。
本研究探讨了围产期母体西式高热量饮食（Western hypercaloric diet, HCD）的程序化效应，及其对成年子代神经元可塑性与心脏代谢健康的影响。
将C57BL/6J品系母鼠在与普通饮食（regular diet, RD）喂养的公鼠交配前，预先饲喂HCD 1个月，并在整个妊娠及哺乳阶段持续维持该饮食模式。子代断乳后，分别饲喂HCD或RD，持续饲养3个月。
母体程序化干预可引发雄性特异性高血压与高血糖，且雌雄子代均表现出血管交感紧张性增强。
令人意外的是，与未接受程序化干预的HCD喂养雄性小鼠相比，接受围产期程序化干预且后续饲喂HCD的雄性子代，其血糖水平更低、胰岛素抵抗程度更轻，瘦素水平也有所降低。
在接受程序化干预的雄性子代下丘脑组织中，参与胶质细胞与星形胶质细胞分化的基因呈现出差异甲基化模式。
在程序化干预的雄性子代体内，参与炎症反应与2型糖尿病发生的基因，可被差异表达的微小RNA（miRNA）所靶向调控。
甲基测序（methyl-seq）数据与我们的研究发现相符：在程序化干预雄性小鼠的室旁核（paraventricular nucleus, PVN）中，存在星形胶质细胞增生、小胶质细胞增生以及小胶质细胞激活增强的现象。
与未接受程序化干预的HCD喂养雄性小鼠相比，接受围产期程序化干预且后续饲喂HCD的雄性小鼠下丘脑组织中转化生长因子β2（TGF-β2）、核因子κB2（NF-κB2）、核因子κBp65（NF-κBp65）、丝氨酸磷酸化胰岛素受体底物1（Ser-pIRS1）以及胰高血糖素样肽1受体（GLP1R）的蛋白表达水平均有所降低，这与程序化干预在HCD雄性小鼠中产生的保护效应相一致。
综上，本研究表明，母体HCD干预可对子代产生程序化效应，引发神经元可塑性改变，并导致雄性特异性高血压与高血糖；与此同时，我们观察到程序化干预可能通过激活代谢通路，使机体更高效地处理过量营养物质，从而发挥代偿性保护作用。
实验整体设计：本数据集的甲基测序（methyl-seq）数据来源于两类小鼠的下丘脑组织：一类为接受围产期高热量饮食程序化干预的小鼠，另一类为未接受程序化干预、仅在出生后饲喂HCD或普通饮食的小鼠。样本命名的前半部分代表母体饮食类型，后半部分代表子代饮食类型。