title: Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice.
abstract: OBJECTIVE
  Obesity induced, non-alcoholic fatty liver disease (NAFLD), is now the major cause in affluent countries, of the spectrum of steatosis-to-cirrhosis. Obesity and NAFLD rates in reproductive age women, and adolescents, are rising worldwide. Our hypothesis was that maternal obesity and lactation transmit to the offspring a pre-disposition to dysmetabolism, obesity and NAFLD.
  
  
  METHODS
  Female mice were fed standard or obesogenic chow, before, throughout pregnancy, and during lactation. The critical developmental period was studied by cross-fostering offspring of lean and obese dams. Offspring were then weaned onto standard chow and studied at 3months. Read-outs included markers of metabolic dysfunction, biochemical and histological indicators of NAFLD, induction of liver fibrogenesis, and activation of pro-fibrotic pathways. Mechanisms involved in programming a dysmetabolic and NAFLD phenotype were investigated by assaying breast milk components.
  
  
  RESULTS
  Offspring of obese dams had a dysmetabolic, insulin resistant and NAFLD phenotype compared to offspring of lean dams. Offspring of lean dams that were suckled by obese dams showed an exaggerated dysmetabolic and NAFLD phenotype, with increased body weight, as well as increased levels of insulin, leptin, aspartate transaminase, interleukin-6, tumour necrosis factor-alpha, liver triglycerides, steatosis, hepatic fibrogenesis, renal norepinephrine, and liver alpha1-D plus beta1-adrenoceptors, indicative of sympathetic nervous system activation. Obese dams also had raised breast milk leptin levels compared to lean dams.
  
  
  CONCLUSIONS
  Maternal obesity programs development of a dysmetabolic and NAFLD phenotype, which is critically dependent on the early postnatal period and possibly involving alteration of hypothalamic appetite nuclei signalling by maternal breast milk and neonatal adipose tissue derived, leptin.
authors.affiliation: University College London, Centre for Hepatology, Royal Free Hospital, London, UK. j.oben@ucl.ac.uk
authors.forename: Jude A
authors.initials: JA
authors.lastname: Oben
authors.forename: Angelina
authors.initials: A
authors.lastname: Mouralidarane
authors.forename: Anne-Maj
authors.initials: AM
authors.lastname: Samuelsson
authors.forename: Phillippa J
authors.initials: PJ
authors.lastname: Matthews
authors.forename: Maelle L
authors.initials: ML
authors.lastname: Morgan
authors.forename: Chad
authors.initials: C
authors.lastname: McKee
authors.forename: Junpei
authors.initials: J
authors.lastname: Soeda
authors.forename: Denise S
authors.initials: DS
authors.lastname: Fernandez-Twinn
authors.forename: Malgorzata S
authors.initials: MS
authors.lastname: Martin-Gronert
authors.forename: Susan E
authors.initials: SE
authors.lastname: Ozanne
authors.forename: Barbara
authors.initials: B
authors.lastname: Sigala
authors.forename: Marco
authors.initials: M
authors.lastname: Novelli
authors.forename: Lucilla
authors.initials: L
authors.lastname: Poston
authors.forename: Paul D
authors.initials: PD
authors.lastname: Taylor
mesh_terms: D000199:Actins / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003094:Collagen / Q000235:genetics; D024042:Collagen Type I; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics; D007774:Lactation; D020738:Leptin / Q000378:metabolism; D024821:Metabolic Syndrome / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008892:Milk / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D000199:Actins; C547717:Adra1b protein, mouse; C547720:Adra1d protein, mouse; D024042:Collagen Type I; D015850:Interleukin-6; D020738:Leptin; D018340:Receptors, Adrenergic, alpha-1; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen