1. Developmental Biology
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Glucocorticoid receptor-PPARα axis in fetal mouse liver prepares neonates for milk lipid catabolism

  1. Gianpaolo Rando
  2. Chek Kun Tan
  3. Nourhène Khaled
  4. Alexandra Montagner
  5. Nicolas Leuenberger
  6. Justine Bertrand-Michel
  7. Eeswari Paramalingam
  8. Hervé Guillou
  9. Walter Wahli  Is a corresponding author
  1. University of Lausanne, Switzerland
  2. Nanyang Technological University, Singapore
  3. INRA, Université de Toulouse, France
  4. IFR 150, INSERM, France
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Cite this article as: eLife 2016;5:e11853 doi: 10.7554/eLife.11853

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.

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Article and author information

Author details

  1. Gianpaolo Rando

    Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Chek Kun Tan

    Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  3. Nourhène Khaled

    Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. 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.
  5. Nicolas Leuenberger

    Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  6. Justine Bertrand-Michel

    Institut Fédératif de Recherche Bio-Médicale de Toulouse, IFR 150, INSERM, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Eeswari Paramalingam

    Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  8. 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.
  9. 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.
    ORCID icon "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.

Reviewing Editor

  1. K VijayRaghavan, Tata Institute of Fundamental Research, India

Publication history

  1. Received: September 25, 2015
  2. Accepted: June 30, 2016
  3. Accepted Manuscript published: July 1, 2016 (version 1)
  4. Accepted Manuscript updated: July 7, 2016 (version 2)
  5. 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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