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Maternal obesity modulates sexually dimorphic epigenetic regulation and expression of leptin receptor in offspring hippocampus
Brain, Behavior, and Immunity ( IF 8.8 ) Pub Date : 2020-08-01 , DOI: 10.1016/j.bbi.2020.03.006
K A Glendining 1 , M B A Higgins 1 , L C Fisher 1 , C L Jasoni 1
Affiliation  

Maternal obesity during pregnancy is associated with a greater risk for obesity and neurodevelopmental deficits in offspring. This developmental programming of disease is proposed to involve neuroendocrine, inflammatory, and epigenetic factors during gestation that disrupt normal fetal brain development. The hormones leptin and insulin are each intrinsically linked to metabolism, inflammation, and neurodevelopment, which led us to hypothesise that maternal obesity may disrupt leptin or insulin receptor signalling in the developing brain of offspring. Using a C57BL/6 mouse model of high fat diet-induced maternal obesity (mHFD), we performed qPCR to examine leptin receptor (Lepr) and insulin receptor (Insr) gene expression in gestational day (GD) 17.5 fetal brain. We found a significant effect of maternal diet and offspring sex on Lepr regulation in the developing hippocampus, with increased Lepr expression in female mHFD offspring (p<0.05) compared to controls. Maternal diet did not alter hippocampal Insr in the fetal brain, or Lepr or Insr in prefrontal cortex, amygdala, or hypothalamus of female or male offspring. Chromatin immunoprecipitation revealed decreased binding of histones possessing the repressive histone mark H3K9me3 at the Lepr promoter (p<0.05) in hippocampus of female mHFD offspring compared to controls, but not in males. Sex-specific deregulation of Lepr could be reproduced in vitro by exposing female hippocampal neurons to the obesity related proinflammatory cytokine IL-6, but not IL-17a or IFNG. Our findings indicate that the obesity-related proinflammatory cytokine IL-6 during pregnancy leads to sexually dimorphic changes in the modifications of histones binding at the Lepr gene promoter, and concomitant changes to Lepr transcription in the developing hippocampus. This suggests that exposure of the fetus to metabolic inflammatory molecules can impact epigenetic regulation of gene expression in the developing hippocampus.

中文翻译:

母体肥胖调节后代海马瘦素受体的性二态表观遗传调控和表达

怀孕期间的母亲肥胖与后代肥胖和神经发育缺陷的风险增加有关。这种疾病的发育程序被提议涉及在妊娠期间破坏正常胎儿大脑发育的神经内分泌、炎症和表观遗传因素。瘦素和胰岛素激素都与新陈代谢、炎症和神经发育有着内在的联系,这使我们假设母体肥胖可能会破坏后代大脑发育中的瘦素或胰岛素受体信号传导。使用高脂肪饮食诱导的母体肥胖 (mHFD) 的 C57BL/6 小鼠模型,我们进行 qPCR 以检查妊娠日 (GD) 17.5 胎儿大脑中的瘦素受体 (Lepr) 和胰岛素受体 (Insr) 基因表达。我们发现母体饮食和后代性别对发育中海马的 Lepr 调节有显着影响,与对照组相比,女性 mHFD 后代的 Lepr 表达增加 (p<0.05)。母体饮食不会改变胎儿大脑中的海马 Insr,或雌性或雄性后代的前额叶皮层、杏仁核或下丘脑中的 Lepr 或 Insr。染色质免疫沉淀显示,与对照组相比,雌性 mHFD 后代海马中具有抑制性组蛋白标记 H3K9me3 的组蛋白在 Lepr 启动子 (p<0.05) 的结合减少,但在雄性中没有。通过将雌性海马神经元暴露于肥胖相关的促炎细胞因子 IL-6 而不是 IL-17a 或 IFNG,可以在体外复制 Lepr 的性别特异性失调。我们的研究结果表明,怀孕期间肥胖相关的促炎细胞因子 IL-6 导致在 Lepr 基因启动子处结合的组蛋白修饰发生两性变化,并伴随着发育中海马体中 Lepr 转录的变化。这表明胎儿暴露于代谢性炎症分子会影响发育中的海马体中基因表达的表观遗传调控。
更新日期:2020-08-01
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