Glucocorticoid receptor-PPARα axis in fetal mouse liver prepares neonates for milk lipid catabolism
- University of Lausanne, Switzerland
- Nanyang Technological University, Singapore
- INRA, Université de Toulouse, France
- IFR 150, INSERM, France
Abstract
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.
Data availability
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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).
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Postnatal PPARa-dependent gene expression in two-days old mouse liverPublicly available at the NCBI Gene Expression Omnibus (Accession no: GSE39670).
Article and author information
Author details
Reviewing Editor
- K VijayRaghavan, Tata Institute of Fundamental Research, India
Ethics
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.
Version history
- Received: September 25, 2015
- Accepted: June 30, 2016
- Accepted Manuscript published: July 1, 2016 (version 1)
- Accepted Manuscript updated: July 7, 2016 (version 2)
- Version of Record published: July 27, 2016 (version 3)
Copyright
© 2016, Rando et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Glucocorticoid receptor-PPARα axis in fetal mouse liver prepares neonates for milk lipid catabolism
eLife 5:e11853.
https://doi.org/10.7554/eLife.11853
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