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 PPARα, 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)-PPARα axis in which GR directly regulates the transcriptional activation of PPARα by binding to its promoter. Certain PPARα target genes such as Fgf21 remain repressed in the fetal liver and become PPARα responsive after birth following an epigenetic switch triggered by β-hydroxybutyrate-mediated inhibition of HDAC3. This study identifies an endocrine developmental axis in which fetal GR primes the activity of PPARα in anticipation of the sudden shifts in postnatal nutrient source and metabolic demands.
Prenatal PPARa-dependent gene expression in fetal mouse liver just before birth (E19.5)Publicly available at the NCBI Gene Expression Omnibus (Accession no: GSE39669).
Postnatal PPARa-dependent gene expression in two-days old mouse liverPublicly available at the NCBI Gene Expression Omnibus (Accession no: GSE39670).
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to the institutional animal care and use committee (IACUC) protocol (#2013/SHS/866) approved by SingHealth, Singapore and the Vaud Cantonal Authority, Switzerland.
- K VijayRaghavan, Tata Institute of Fundamental Research, India
© 2016, Rando et al.
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