Embryonic exposure to hyper glucocorticoids suppresses brown fat development and thermogenesis via REDD1.

Maternal stress during pregnancy is prevailing worldwide, which exposes fetuses to intrauterine hyper glucocorticoids (GC), programming offspring to obesity and metabolic diseases. Despite the importance of brown adipose tissue (BAT) in maintaining long-term metabolic health, impacts of prenatal hyper GC on postnatal BAT thermogenesis and underlying regulations remain poorly defined. Pregnant mice were administrated with synthetic GC dexamethasone (DEX) at levels comparable to fetal GC exposure of stressed mothers. Prenatal GC exposure dose-dependently reduced BAT thermogenic activity, contributing to lower body temperature and higher mortality of neonates; such difference was abolished under thermoneutrality, underscoring BAT deficiency was the major contributor to adverse changes in postnatal thermogenesis due to excessive GC. Prenatal GC exposure highly activated Redd1 expression and reduced Ppargc1a transcription from the alternative promoter (Ppargc1a-AP) in neonatal BAT. During brown adipocyte differentiation, ectopic Redd1 expression reduced Ppargc1a-AP expression and mitochondrial biogenesis; and the inhibitory effects of GC on mitochondrial biogenesis and Ppargc1a-AP expression were blocked by Redd1 ablation. Redd1 reduced protein kinase A phosphorylation and suppressed cyclic adenosine monophosphate (cAMP) -responsive element-binding protein (CREB) binding to the cAMP regulatory element (CRE) in Ppargc1a-AP promoter, leading to Ppargc1a-AP inactivation. In summary, excessive maternal GC exposure during pregnancy dysregulates Redd1-Ppargc1a-AP axis, which impairs fetal BAT development, hampering postnatal thermogenic adaptation and metabolic health of offspring.

孕期母体应激在全球普遍存在，这使胎儿暴露于宫内高糖皮质激素（GC）环境中，使后代易患肥胖和代谢疾病。尽管棕色脂肪组织（BAT）在维持长期代谢健康方面很重要，但产前高GC对产后BAT产热的影响及其潜在的调节机制仍不明确。给怀孕小鼠施用合成的糖皮质激素地塞米松（DEX），其剂量与应激母体的胎儿GC暴露水平相当。产前GC暴露呈剂量依赖性地降低BAT产热活性，导致新生小鼠体温降低和死亡率升高；在热中性条件下这种差异消失，这强调了BAT缺陷是过量GC导致产后产热不良变化的主要原因。产前GC暴露高度激活新生BAT中的Redd1表达，并降低来自选择性启动子（Ppargc1a - AP）的Ppargc1a转录。在棕色脂肪细胞分化过程中，异位的Redd1表达降低Ppargc1a - AP表达和线粒体生物发生；并且GC对线粒体生物发生和Ppargc1a - AP表达的抑制作用可通过Redd1敲除来阻断。Redd1降低蛋白激酶A磷酸化，并抑制环磷酸腺苷（cAMP）反应元件结合蛋白（CREB）与Ppargc1a - AP启动子中的cAMP调节元件（CRE）结合，导致Ppargc1a - AP失活。总之，孕期母体过量的GC暴露会失调Redd1 - Ppargc1a - AP轴，这会损害胎儿BAT发育，阻碍后代产后的产热适应和代谢健康。