Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA.
School of Food Sciences, Washington State University, Pullman, WA.
Diabetes. 2020 Aug;69(8):1662-1674. doi: 10.2337/db20-0009. Epub 2020 May 14.
Maternal stress during pregnancy exposes fetuses to hyperglucocorticoids, which increases the risk of metabolic dysfunctions in offspring. Despite being a key tissue for maintaining metabolic health, the impacts of maternal excessive glucocorticoids (GC) on fetal brown adipose tissue (BAT) development and its long-term thermogenesis and energy expenditure remain unexamined. For testing, pregnant mice were administered dexamethasone (DEX), a synthetic GC, in the last trimester of gestation, when BAT development is the most active. DEX offspring had glucose, insulin resistance, and adiposity and also displayed cold sensitivity following cold exposure. In BAT of DEX offspring, expression was suppressed, together with reduced mitochondrial density, and the brown progenitor cells sorted from offspring BAT demonstrated attenuated brown adipogenic capacity. Increased DNA methylation in promoter had a fetal origin; elevated DNA methylation was also detected in neonatal BAT and brown progenitors. Mechanistically, fetal GC exposure increased GC receptor/DNMT3b complex in binding to the promoter, potentially driving its de novo DNA methylation and transcriptional silencing, which impaired fetal BAT development. In summary, maternal GC exposure during pregnancy increases DNA methylation in the promoter, which epigenetically impairs BAT thermogenesis and energy expenditure, predisposing offspring to metabolic dysfunctions.
孕期母体应激会使胎儿暴露于高糖皮质激素环境中，这增加了后代代谢功能紊乱的风险。尽管棕色脂肪组织（BAT）是维持代谢健康的关键组织，但母体过量糖皮质激素（GC）对胎儿棕色脂肪组织（BAT）发育及其长期产热和能量消耗的影响仍未被研究。为了进行测试，在妊娠最后三个月给怀孕的老鼠注射地塞米松（DEX），这是一种合成 GC，此时 BAT 发育最为活跃。DEX 后代表现出葡萄糖、胰岛素抵抗和肥胖，并且在暴露于寒冷后表现出冷敏感。在 DEX 后代的 BAT 中，UCP1 表达受到抑制，同时线粒体密度降低，并且从后代 BAT 中分离出的棕色祖细胞显示出减弱的棕色脂肪生成能力。UCP1 启动子中的 DNA 甲基化增加具有胎儿起源；在新生儿 BAT 和棕色祖细胞中也检测到升高的 DNA 甲基化。从机制上讲，胎儿 GC 暴露会增加 GC 受体/DNMT3b 复合物与 UCP1 启动子的结合，可能导致其从头 DNA 甲基化和转录沉默，从而损害胎儿 BAT 发育。总之，孕期母体 GC 暴露会增加 UCP1 启动子中的 DNA 甲基化，这种表观遗传修饰会损害 BAT 的产热和能量消耗，使后代易患代谢功能紊乱。
