title: Maternal obesity programs offspring non-alcoholic fatty liver disease through disruption of 24-h rhythms in mice.
abstract: BACKGROUND
  Maternal obesity increases offspring propensity to metabolic dysfunctions and to non-alcoholic fatty liver disease (NAFLD), which may lead to cirrhosis or liver cancer. The circadian clock is a transcriptional/epigenetic molecular machinery synchronising physiological processes to coordinate energy utilisation within a 24-h light/dark period. Alterations in rhythmicity have profound effects on metabolic pathways, which we sought to investigate in offspring with programmed NAFLD.
  
  
  METHODS
  Mice were fed a standard or an obesogenic diet (OD), before and throughout pregnancy, and during lactation. Offspring were weaned onto standard or an OD at 3 weeks postpartum and housed in 12:12 light/dark conditions. Biochemical and histological indicators of NAFLD and fibrosis, analysis of canonical clock genes with methylation status and locomotor activity were investigated at 6 months.
  
  
  RESULTS
  We show that maternal obesity interacts with an obesogenic post-weaning diet to promote the development of NAFLD with disruption of canonical metabolic rhythmicity gene expression in the liver. We demonstrate hypermethylation of BMAL-1 (brain and muscle Arnt like-1) and Per2 promoter regions and altered 24-h rhythmicity of hepatic pro-inflammatory and fibrogenic mediators.
  
  
  CONCLUSIONS
  These data implicate disordered circadian rhythms in NAFLD and suggest that disruption of this system during critical developmental periods may be responsible for the onset of chronic liver disease in adulthood.
authors.affiliation: Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.|Women's Health Academic Centre, King's College London, St Thomas' Hospital, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Mouralidarane
authors.affiliation: Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Soeda
authors.affiliation: Women's Health Academic Centre, King's College London, St Thomas' Hospital, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Sugden
authors.affiliation: Women's Health Academic Centre, King's College London, St Thomas' Hospital, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Bocianowska
authors.affiliation: Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Carter
authors.affiliation: Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ray
authors.affiliation: Histopathology Department, University College Hospital, University College London, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Saraswati
authors.affiliation: Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Cordero
authors.affiliation: Histopathology Department, University College Hospital, University College London, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Novelli
authors.affiliation: Department of Liver Medicine and Transplant, Sheila Sherlock Liver Centre, University College London, Royal Free Hospital, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Fusai
authors.affiliation: Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.|Gastroenterology Unit, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.|School of Science and Technology, Nottingham Trent University, Nottingham, UK.
authors.forename: M
authors.initials: M
authors.lastname: Vinciguerra
authors.affiliation: Women's Health Academic Centre, King's College London, St Thomas' Hospital, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Poston
authors.affiliation: Women's Health Academic Centre, King's College London, St Thomas' Hospital, London, UK.
authors.forename: P D
authors.initials: PD
authors.lastname: Taylor
authors.affiliation: Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Oben
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002940:Circadian Rhythm; D019175:DNA Methylation; D004195:Disease Models, Animal; D005260:Female; D007774:Lactation; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000378:metabolism*; D056950:Period Circadian Proteins / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins