摘要
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 Ppargc1 a transcription from the alternative promoter(Ppargc1 a-AP) in neonatal BAT. During brown adipocyte differentiation, ectopic Redd1 expression reduced Ppargc1 a-AP expression and mitochondrial biogenesis;and the inhibitory effects of GC on mitochondrial biogenesis and Ppargc1 a-AP expression were blocked by Redd1 ablation. Redd1 reduced protein kinase A phosphorylation and suppressed cyclic adenosine monophosphate(c AMP)-responsive element-binding protein(CREB) binding to the c AMP regulatory element(CRE) in Ppargc1 a-AP promoter, leading to Ppargc1 a-AP inactivation. In summary, excessive maternal GC exposure during pregnancy dysregulates Redd1-Ppargc1 a-AP axis, which impairs fetal BAT development, hampering postnatal thermogenic adaptation and metabolic health of offspring.
母体应激导致子宫内糖皮质激素升高,增加后代能量代谢紊乱和肥胖风险.尽管棕色脂肪对于维护机体正常代谢和产热极其重要,但是子宫内过量糖皮质激素是否会影响后代棕色脂肪发育、线粒体解偶联产热及其调控机制,目前缺乏研究.本文通过对怀孕老鼠注射与母体应激相同剂量的糖皮质激素,发现伴随着激活棕色脂肪中糖皮质激素受体响应蛋白REDD1,胎儿和新生儿不仅表现出棕色脂肪发育障碍、体温和存活率下降,而且棕色脂肪中Ppargc1a替代性启动子转录水平以及线粒体合成显著降低.在诱导胚胎成纤维细胞分化成棕色脂肪细胞过程中,通过敲降和过表达Redd1和Ppargc1a,进一步发现REDD1会抑制PKA-CREB蛋白磷酸化,降低了CREB蛋白与Ppargc1a替代性启动子cAMP调控元件的结合,导致棕色脂肪细胞分化、线粒体合成和解偶联产热功能受损.本研究揭示了在孕期过量糖皮质激素条件下, Redd1抑制Ppargc1a替代性启动子表达和棕色脂肪细胞分化,引起后代线粒体产热障碍和能量代谢紊乱,为药物研发以促进胎儿正常发育提供了新思路.
基金
This work was supported by the National Institute of Health(NIH R01-HD067449)。
