title: The direction of cross affects [corrected] obesity after puberty in male but not female offspring.
abstract: BACKGROUND
  We investigated parent-of-origin and allele-specific expression effects on obesity and hepatic gene expression in reciprocal crosses between the Berlin Fat Mouse Inbred line (BFMI) and C57Bl/6NCrl (B6N).
  
  
  RESULTS
  We found that F1-males with a BFMI mother developed 1.8 times more fat mass on a high fat diet at 10 weeks than F1-males of a BFMI father. The phenotype was detectable from six weeks on and was preserved after cross-fostering. RNA-seq data of liver provided evidence for higher biosynthesis and elongation of fatty acids (p = 0.00635) in obese male offspring of a BFMI mother versus lean offspring of a BFMI father. Furthermore, fatty acid degradation (p = 0.00198) and the peroxisome pathway were impaired (p = 0.00094). The circadian rhythm was affected as well (p = 0.00087). Among the highest up-regulated protein coding genes in obese males were Acot4 (1.82 fold, p = 0.022), Cyp4a10 (1.35 fold, p = 0.026) and Cyp4a14 (1.32 fold, p = 0.012), which hydroxylize fatty acids and which are known to be increased in liver steatosis. Obese males showed lower expression of the genetically imprinted and paternally expressed 3 (Peg3) gene (0.31 fold, p = 0.046) and higher expression of the androgen receptor (Ar) gene (2.38 fold, p = 0.068). Allelic imbalance was found for expression of ATP-binding cassette transporter gene Abca8b. Several of the differentially expressed genes contain estrogen response elements.
  
  
  CONCLUSIONS
  Parent-of-origin effects during gametogenesis and/or fetal development in an obese mother epigenetically modify the transcription of genes that lead to enhanced fatty acid synthesis and impair β-oxidation in the liver of male, but not female F1 offspring. Down-regulation of Peg3 could contribute to trigger this metabolic setting. At puberty, higher amounts of the androgen receptor and altered access to estrogen response elements in affected genes are likely responsible for male specific expression of genes that were epigenetically triggered. A suggestive lack of estrogen binding motifs was found for highly down-regulated genes in adult hepatocytes of obese F1 males (p = 0.074).
authors.affiliation: Albrecht Daniel Thaer-Institut für Agrar- und Gartenbauwissenschaften, Humboldt-Universität zu Berlin, Invalidenstraße 42, D-10115, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kärst
authors.affiliation: Albrecht Daniel Thaer-Institut für Agrar- und Gartenbauwissenschaften, Humboldt-Universität zu Berlin, Invalidenstraße 42, D-10115, Berlin, Germany.
authors.forename: Danny
authors.initials: D
authors.lastname: Arends
authors.affiliation: Albrecht Daniel Thaer-Institut für Agrar- und Gartenbauwissenschaften, Humboldt-Universität zu Berlin, Invalidenstraße 42, D-10115, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Heise
authors.affiliation: Albrecht Daniel Thaer-Institut für Agrar- und Gartenbauwissenschaften, Humboldt-Universität zu Berlin, Invalidenstraße 42, D-10115, Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Trost
authors.affiliation: Max Planck Institute for Molecular Genetics, Gene Regulation and Systems Biology of Cancer, Ihnestraße 63-73, 14195, Berlin, Germany.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Yaspo
authors.affiliation: Max Planck Institute for Molecular Genetics, Gene Regulation and Systems Biology of Cancer, Ihnestraße 63-73, 14195, Berlin, Germany.
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Amstislavskiy
authors.affiliation: Max Planck Institute for Molecular Genetics, Gene Regulation and Systems Biology of Cancer, Ihnestraße 63-73, 14195, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Risch
authors.affiliation: Max Planck Institute for Molecular Genetics, Gene Regulation and Systems Biology of Cancer, Ihnestraße 63-73, 14195, Berlin, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.affiliation: Albrecht Daniel Thaer-Institut für Agrar- und Gartenbauwissenschaften, Humboldt-Universität zu Berlin, Invalidenstraße 42, D-10115, Berlin, Germany. gudrun.brockmann@agrar.hu-berlin.de.
authors.forename: Gudrun A
authors.initials: GA
authors.lastname: Brockmann
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000235:genetics*; D011627:Puberty / Q000235:genetics
chemical_list: D005227:Fatty Acids