title: Fetal Hyperglycemia Changes Human Preadipocyte Function in Adult Life.
abstract: Offspring of women with gestational diabetes (O-GDM) or type 1 diabetes mellitus (O-T1DM) have been exposed to hyperglycemia in utero and have an increased risk of developing metabolic disease in adulthood.
  
  
  
  In total, we recruited 206 adult offspring comprising the two fetal hyperglycemic groups, O-GDM and O-T1DM, and, as a control group, offspring from the background population (O-BP). Subcutaneous fat biopsies were obtained and preadipocyte cell cultures were established from adult male O-GDM (n = 18, age 30.1 ± 2.5 years), O-T1DM (n = 18, age 31.6 ± 2.2 years), and O-BP (n = 16; age, 31.5 ± 2.7 years) and cultured in vitro.
  
  
  
  First, we studied in vivo adipocyte histology. Second, we studied in vitro preadipocyte leptin secretion, gene expression, and LEP DNA methylation. This was studied in combination with in vitro preadipocyte lipogenesis, lipolysis, and mitochondrial respiration.
  
  
  
  We show that subcutaneous adipocytes from O-GDM are enlarged compared with O-BP adipocytes. Preadipocytes isolated from male O-GDM and O-T1DM and cultured in vitro displayed decreased LEP promoter methylation, increased leptin gene expression, and elevated leptin secretion throughout differentiation, compared with adipocytes established from male O-BP. In addition, the preadipocytes demonstrated functional defects including decreased maximal mitochondrial capacity with increased lipolysis and decreased ability to store fatty acids when challenged with 3 days of extra fatty acid supply.
  
  
  
  Taken together, these findings show that intrinsic epigenetic and functional changes exist in preadipocyte cultures from individuals exposed to fetal hyperglycemia who are at increased risk of developing metabolic disease.
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, 2200 Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 1165 Denmark.|Danish PhD School of Molecular Metabolism, Odense, 5000 Denmark.
authors.forename: Ninna Schiøler
authors.initials: NS
authors.lastname: Hansen
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, 2200 Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 1165 Denmark.
authors.forename: Klaudia Stanislawa
authors.initials: KS
authors.lastname: Strasko
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, 2200 Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 1165 Denmark.|The Danish Diabetes Academy, Odense, 5000 Denmark.
authors.forename: Line
authors.initials: L
authors.lastname: Hjort
authors.affiliation: Center for Pregnant Women with Diabetes, Department of Obstetrics, Copenhagen, 2200 Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Kelstrup
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, 2200 Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 1165 Denmark.|Center for Pregnant Women with Diabetes, Department of Obstetrics, Copenhagen, 2200 Denmark.|Novo Nordisk A/S, Søborg, 2860 Denmark.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Houshmand-Øregaard
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, 2200 Denmark.|The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, 2200 Denmark.
authors.forename: Maren
authors.initials: M
authors.lastname: Schrölkamp
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, 2200 Denmark.
authors.forename: Heidi Schiøler
authors.initials: HS
authors.lastname: Schultz
authors.affiliation: Global Research, Novo Nordisk A/S, Måløv, 2760 Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Scheele
authors.affiliation: Global Research, Novo Nordisk A/S, Måløv, 2760 Denmark.
authors.forename: Bente Klarlund
authors.initials: BK
authors.lastname: Pedersen
authors.affiliation: Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, CRC, Malmö, SE-221 00 Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ling
authors.affiliation: Department of Obstetrics and Gynecology, Hilleroed Hospital, Hilleroed, 3400 Denmark.
authors.forename: Tine Dalsgaard
authors.initials: TD
authors.lastname: Clausen
authors.affiliation: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 1165 Denmark.|Center for Pregnant Women with Diabetes, Department of Obstetrics, Copenhagen, 2200 Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Damm
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, 2200 Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 1165 Denmark.|Astra Zeneca, Göteborg, SE-431 50 Sweden.
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, 2200 Denmark.
authors.forename: Christa
authors.initials: C
authors.lastname: Broholm
mesh_terms: D017667:Adipocytes / Q000502:physiology*; D000328:Adult; D032721:Adult Children; D016022:Case-Control Studies; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology; D016640:Diabetes, Gestational; D004198:Disease Susceptibility; D005260:Female; D005315:Fetal Diseases / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006943:Hyperglycemia / Q000151:congenital* / Q000378:metabolism / Q000503:physiopathology; D008066:Lipolysis / Q000502:physiology; D008297:Male; D011247:Pregnancy; D011254:Pregnancy in Diabetics; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism / Q000503:physiopathology*; D012307:Risk Factors