title: Glucocorticoid receptor-PPARα axis in fetal mouse liver prepares neonates for milk lipid catabolism.
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.
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Rando
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, , Singapore.
authors.forename: Chek Kun
authors.initials: CK
authors.lastname: Tan
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Nourhène
authors.initials: N
authors.lastname: Khaled
authors.affiliation: UMR 1331 ToxAlim Research Centre in Food Toxicology, INRA, Université de Toulouse, Toulouse, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Montagner
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Leuenberger
authors.affiliation: IFR 150 Plateforme Metatoul, Institut Fédératif de Recherche Bio-Médicale de Toulouse INSERM U563, Toulouse, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Bertrand-Michel
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, , Singapore.
authors.forename: Eeswari
authors.initials: E
authors.lastname: Paramalingam
authors.affiliation: UMR 1331 ToxAlim Research Centre in Food Toxicology, INRA, Université de Toulouse, Toulouse, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Guillou
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.|Lee Kong Chian School of Medicine, Nanyang Technological University, , Singapore.|UMR 1331 ToxAlim Research Centre in Food Toxicology, INRA, Université de Toulouse, Toulouse, France.
authors.forename: Walter
authors.identifier: 0000-0002-5966-9089
authors.initials: W
authors.lastname: Wahli
mesh_terms: D000818:Animals; D004734:Energy Metabolism; D018507:Gene Expression Regulation, Developmental; D050356:Lipid Metabolism; D008099:Liver / Q000196:embryology*; D008660:Metabolism; D051379:Mice; D008892:Milk / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
chemical_list: D047493:PPAR alpha; D011965:Receptors, Glucocorticoid
keywords: FGF21; HDAC3; PPARα; developmental biology; glucocorticoid receptor; hepatic steatosis; ketone body; mouse; stem cells