Excessive glucocorticoids during pregnancy impair fetal brown fat development and predisposes offspring to metabolic dysfunctions

Maternal stress during pregnancy exposes fetuses to hyper glucocorticoids (GC), which increases the risk of metabolic dysfunctions in offspring. Despite of being a key tissue for maintaining metabolic health, the impacts of maternal excessive GC on fetal brown adipose tissue (BAT) development and its long-term thermogenesis and energy expenditure remain unexamined. To test, pregnant mice were administrated with 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, also displayed cold sensitivity following cold exposure. In BAT of DEX offspring, Ppargc1a 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 Ppargc1a promoter had a fetal origin because elevated DNA methylation was also detected in neonatal BAT and brown progenitors. Mechanistically, fetal GC exposure increased GC receptor (GR)/ DNMT3b complex in binding to the Ppargc1a 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 Ppargc1a promoter, which epigenetically impairs BAT thermogenesis and energy expenditure, predisposing offspring to metabolic dysfunctions.