Maternal Western Diet Programs Cardiometabolic Dysfunction and Hypothalamic Inflammation via Epigenetic Mechanisms Predominantly in the Male Offspring [Methyl-seq]. 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 TGFβ2, NF-κB2, NF-κBp65, 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.

孕期母体暴露情况是子代健康结局的重要决定因素。此类暴露可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方高能量饮食（Western hypercaloric diet, HCD）程序化效应，及其对成年子代神经元可塑性与心血管代谢健康的影响。实验中将C57BL/6J品系雌鼠在与饲喂常规饮食（Regular Diet, RD）的雄鼠交配前，先饲喂HCD1个月，并在整个妊娠与哺乳期间持续维持该饮食方案。子代断奶后，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升高。令人意外的是，相较于未接受程序化干预的HCD饲喂雄性小鼠，接受程序化干预并饲喂HCD的雄性子代小鼠血糖水平更低，胰岛素抵抗程度与瘦素水平均显著降低。程序化干预的雄性子代小鼠下丘脑中，参与胶质细胞与星形胶质细胞分化的基因呈现差异化甲基化修饰。程序化干预的雄性子代小鼠体内，与炎症及2型糖尿病相关的基因受到差异表达微小RNA（microRNA, miRNA）的调控。甲基化测序（Methyl-seq）数据得到了以下发现的验证：程序化干预的雄性小鼠室旁核（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HCD饲喂的未程序化干预雄性小鼠相比，接受程序化干预并饲喂HCD的雄性小鼠下丘脑中TGFβ2、NF-κB2、NF-κBp65、Ser-pIRS1及GLP1R的蛋白水平显著降低，这与程序化干预为其带来的保护效应相一致。综上，本研究表明母体HCD可对子代产生程序化干预效应，影响其神经元可塑性，并引发雄性特异性高血压与高血糖；与此同时，我们发现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：本数据集的甲基化测序数据来源于两类小鼠的下丘脑组织：一类为围产期饲喂高能量饮食的程序化干预小鼠，另一类为出生后饲喂HCD或常规饮食的未程序化干预小鼠。样本命名的前半部分代表母体饮食，后半部分代表子代饮食。