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.

怀孕期间的母体压力在世界范围内普遍存在，这使胎儿暴露于宫内高糖皮质激素 (GC) 中，使后代患上肥胖症和代谢疾病。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 产热和潜在调节的影响仍不清楚。给怀孕的小鼠注射合成的 GC 地塞米松 (DEX)，其水平与压力母亲的胎儿 GC 暴露水平相当。产前 GC 暴露剂量依赖性地降低 BAT 产热活性，导致新生儿体温降低和死亡率升高；这种差异在热中性条件下被消除，强调 BAT 缺乏是由于过度 GC 导致产后产热产生不利变化的主要原因。Redd1表达和减少来自新生儿 BAT 中替代启动子 ( Ppargc1a -AP) 的Ppargc1a转录。在棕色脂肪细胞分化过程中，异位Redd1表达降低了 Ppargc1a -AP 表达和线粒体生物发生；GC 对线粒体生物发生和Ppargc1a -AP 表达的抑制作用被Redd1消融阻断。Redd1降低蛋白激酶 A 磷酸化并抑制环磷酸腺苷 (cAMP) - 响应元件结合蛋白 (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 GC 过度暴露会使 Redd1 - Ppargc1a -AP 轴失调，从而损害胎儿 BAT 发育，阻碍产后产热适应和后代的代谢健康。