Preclinical studies reveal maternal exercise as a promising intervention to reduce the transmission of multigenerational metabolic dysfunction caused by maternal obesity. The benefits of maternal exercise on offspring health may arise from multiple factors and have recently been shown to involve DNA demethylation of critical hepatic genes leading to enhanced glucose metabolism in offspring. Histone modification is another epigenetic regulator, yet the effects of maternal obesity and exercise on histone methylation in offspring are not known. Here, we find that maternal high-fat diet (HFD; 60% kcal from fat) induced dysregulation of offspring liver glucose metabolism in C57BL/6 mice through a mechanism involving increased reactive oxygen species, WD repeat-containing 82 (WDR82) carbonylation, and inactivation of histone H3 lysine 4 (H3K4) methyltransferase leading to decreased H3K4me3 at the promoters of glucose metabolic genes. Remarkably, the entire signal was restored if the HFD-fed dams had exercised during pregnancy. WDR82 overexpression in hepatoblasts mimicked the effects of maternal exercise on H3K4me3 levels. Placental superoxide dismutase 3 (SOD3), but not antioxidant treatment with N-acetylcysteine was necessary for the regulation of H3K4me3, gene expression, and glucose metabolism. Maternal exercise regulates a multicomponent epigenetic system in the fetal liver resulting in the transmission of the benefits of exercise to offspring.

中文翻译：

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母亲运动诱导的 SOD3 通过稳定 H3K4me3 和防止 WDR82 羰基化来逆转母亲高脂肪饮食对后代代谢的有害影响

临床前研究表明，母亲运动是一种很有前途的干预措施，可以减少母亲肥胖引起的多代代谢功能障碍的传播。母体运动对后代健康的好处可能来自多种因素，最近显示涉及关键肝脏基因的 DNA 去甲基化，从而导致后代葡萄糖代谢增强。组蛋白修饰是另一种表观遗传调节因子，但母亲肥胖和运动对后代组蛋白甲基化的影响尚不清楚。在这里，我们发现母体高脂肪饮食（HFD；60% kcal 来自脂肪）通过一种机制诱导 C57BL/6 小鼠后代肝脏葡萄糖代谢失调，其机制涉及增加活性氧、含有 WD 重复序列的 82 (WDR82) 羰基化、组蛋白 H3 赖氨酸 4 (H3K4) 甲基转移酶失活导致葡萄糖代谢基因启动子 H3K4me3 减少。值得注意的是，如果喂食 HFD 的水坝在怀孕期间进行了锻炼，整个信号就会恢复。WDR82 在成肝细胞中的过表达模拟了母体运动对 H3K4me3 水平的影响。胎盘超氧化物歧化酶 3 (SOD3)，而不是 N-乙酰半胱氨酸的抗氧化处理对于 H3K4me3、基因表达和葡萄糖代谢的调节是必需的。母亲运动调节胎儿肝脏中的多组分表观遗传系统，从而将运动的益处传递给后代。WDR82 在成肝细胞中的过表达模拟了母体运动对 H3K4me3 水平的影响。胎盘超氧化物歧化酶 3 (SOD3)，而不是 N-乙酰半胱氨酸的抗氧化处理对于 H3K4me3、基因表达和葡萄糖代谢的调节是必需的。母亲运动调节胎儿肝脏中的多组分表观遗传系统，从而将运动的益处传递给后代。WDR82 在成肝细胞中的过表达模拟了母体运动对 H3K4me3 水平的影响。胎盘超氧化物歧化酶 3 (SOD3)，而不是 N-乙酰半胱氨酸的抗氧化处理对于 H3K4me3、基因表达和葡萄糖代谢的调节是必需的。母亲运动调节胎儿肝脏中的多组分表观遗传系统，从而将运动的益处传递给后代。