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

妊娠期母体暴露是子代健康结局的关键决定因素。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变化。
本研究探讨了围产期母体饲喂西方高热量饮食（HCD）的程序化效应，及其对成年子代神经元可塑性与心血管代谢健康的影响。
本研究将C57BL/6J品系母鼠在交配前1个月饲喂HCD，随后与饲喂常规饮食（RD）的公鼠交配，并在整个妊娠与哺乳期间持续保持该饮食模式。断乳后，子代小鼠分别饲喂HCD或RD，持续3个月。
母体饮食程序化可引发雄性子代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。
出乎意料的是，相较于未接受程序化处理且饲喂HCD的雄性小鼠，经程序化处理且饲喂HCD的雄性子代血糖水平更低，胰岛素抵抗与瘦素水平均有所降低。
程序化雄性子代下丘脑内参与胶质细胞与星形胶质细胞分化的基因呈现差异甲基化特征。
参与炎症反应与2型糖尿病发病的基因，在程序化雄性子代中被差异表达的miRNA（微小RNA）所靶向调控。
甲基化测序（methyl-seq）数据与我们的观测结果一致：程序化雄性小鼠下丘脑室旁核（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活化增强的现象。
与HCD饲喂雄性小鼠中程序化诱导的保护效应相契合，我们观测到程序化雄性小鼠下丘脑内转化生长因子β2（TGFβ2）、核因子κB2（NF-κB2）、核因子κBp65（NF-κBp65）、磷酸化丝氨酸胰岛素受体底物1（Ser-pIRS1）及胰高血糖素样肽1受体（GLP1R）的蛋白水平，相较于未接受程序化处理且饲喂HCD的雄性小鼠显著降低。
综上，本研究表明，母体饲喂HCD可对子代产生程序化效应，改变其神经元可塑性，并引发雄性子代特异性高血压与高血糖。另一方面，我们观测到程序化效应可能存在代偿作用，即通过激活代谢通路以更高效地处理过量营养物质。
整体实验设计：本研究的mRNA测序数据来源于围产期饲喂高热量饮食的程序化小鼠，以及分别饲喂产后HCD或常规饮食的非程序化小鼠的下丘脑组织。样本名称的第一部分代表母体饮食，第二部分代表子代饮食。