Glucocorticoid receptor-PPARα axis in fetal mouse liver prepares neonates for milk lipid catabolism

In mammals, hepatic lipid catabolism is essential for the newborns to efficiently use milk fat as an energy source. However, it is unclear how this critical trait is acquired and regulated. We demonstrate that under the control of PPAR alpha, the genes required for lipid catabolism are transcribed before birth so that the neonatal liver has a prompt capacity to extract energy from milk upon suckling. The mechanism involves a fetal glucocorticoid receptor (GR)-PPAR alpha axis in which GR directly regulates the transcriptional activation of PPAR alpha by binding to its promoter. Certain PPAR alpha target genes such as Fgf21 remain repressed in the fetal liver and become PPARa responsive after birth following an epigenetic switch triggered by beta-hydroxybutyrate-mediated inhibition of HDAC3. This study identifies an endocrine developmental axis in which fetal GR primes the activity of PPAR alpha in anticipation of the sudden shifts in postnatal nutrient source and metabolic demands.