- (1) Danish PhD School of Molecular Metabolism, Odense, 5000 Denmark.
- (2) University of Copenhagen, grid.5254.6, KU
- (3) Rigshospitalet, grid.475435.4, Capital Region
- (4) Danish Diabetes Academy, grid.484078.7
- (5) Center for Pregnant Women with Diabetes, Department of Obstetrics, Copenhagen, 2200 Denmark.
- (6) Novo Nordisk A/S, Søborg, 2860 Denmark.
- (7) The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, 2200 Denmark.
- (8) Novo Nordisk (Denmark), grid.425956.9
- (9) Lund University, grid.4514.4
- (10) Department of Obstetrics and Gynecology, Hilleroed Hospital, Hilleroed, 3400 Denmark.
- (11) Astra Zeneca, Göteborg, SE-431 50 Sweden.
Context: 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. Design: 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. Main Outcome Measures: 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. Results: 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. Conclusions: 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.