Maternal high-fat high-energy diet impairs surfactant maturation in the non-human primate fetal lung.

Abstract

Due to the global obesity crisis, increasing numbers of women enter pregnancy with overweight or obesity. Their offspring are at greater risk of respiratory complications at birth due to metabolic changes that impact lung development that may reduce capacity for surfactant production. We hypothesize that a high-fat-high-energy diet (HF-HED) negatively impacts late gestation fetal lung development. Female baboons were randomly assigned to Control (metabolizable energy content, MEC = 3.07 kcal/g, 12% from fat; n = 5 M, 3 F fetuses) or high-fat high-energy diet (MEC = 4.03 kcal/g, 45% energy from fat; n = 6 M, 6 F fetuses) before and throughout pregnancy. Fetal lung tissue was collected at 0.9 gestation (term, 184 d). qRT-PCR and immunohistochemistry were utilized to measure expression of key molecules involved in surfactant maturation, the transition to air breathing. HF-HED decreased fetal type-II alveolar epithelial cells and reduced lung surfactant protein expression (SFTPB, SFTPC, and SFTPD). The rate-limiting genes involved in surfactant phospholipid production PCY1TA and ABCA3 was reduced. Genes involved in water (AQP1) and sodium (ATP1A1 and SCNN1B) transport were also downregulated, indicating impaired lung liquid reabsorption. These data indicate that a maternal obesogenic diet impairs surfactant maturation and reduces the capacity for lung liquid reabsorption, increasing the risk of neonatal respiratory complications. Summary of changes within the fetal lung due to exposure to a HF-HED throughout pregnancy. Surfactant maturation was negatively impacted, with a reduction in type II alveolar epithelial cell numbers, reduced mRNA expression in rate limiting enzymes in the production of surfactant phospholipids (PCYT1A, ABCA3), and reduced mRNA expression of surfactant proteins (SFTPB, SFTPC, SFTPD). There was also reduced mRNA expression of sodium transporters (ATP1A1 and SCNN1) which would potentially negatively impact lung liquid reabsorption. Glucose and fatty acid metabolism were dysregulated in the fetal lung with downregulation of glucose transporter 1 (GLUT1) but upregulation of insulin-dependent-glucose and fatty acid transporters (GLUT4, FATP1) and fatty acid synthesis (FASN).