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

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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

The following data sets were generated

(2016) 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).

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE39669
(2016) Postnatal PPARa-dependent gene expression in two-days old mouse liver
Publicly available at the NCBI Gene Expression Omnibus (Accession no: GSE39670).

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE39670

Article and author information

Author details

Gianpaolo Rando

Center for Integrative Genomics, University of Lausanne, Lausanne, Swaziland

Competing interests
The authors declare that no competing interests exist.
Chek Kun Tan

Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

Competing interests
The authors declare that no competing interests exist.
Nourhène Khaled

Center for Integrative Genomics, University of Lausanne, Lausanne, Swaziland

Competing interests
The authors declare that no competing interests exist.
Alexandra Montagner

UMR 1331 TOXALIM Research Centre in Food Toxicology, INRA, Université de Toulouse, Toulouse, France

Competing interests
The authors declare that no competing interests exist.
Nicolas Leuenberger

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

Competing interests
The authors declare that no competing interests exist.
Justine Bertrand-Michel

Institut Fédératif de Recherche Bio-Médicale de Toulouse, INSERM IFR 150 - Institut Fédératif de Recherche Bio-Médicale de Toulouse, Toulouse, France

Competing interests
The authors declare that no competing interests exist.
Eeswari Paramalingam

Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

Competing interests
The authors declare that no competing interests exist.
Hervé Guillou

UMR 1331 TOXALIM Research Centre in Food Toxicology, INRA, Université de Toulouse, Toulouse, France

Competing interests
The authors declare that no competing interests exist.
Walter Wahli

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

For correspondence
walter.wahli@ntu.edu.sg

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5966-9089

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.

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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.