title: Consequences of a Maternal High-Fat Diet and Late Gestation Diabetes on the Developing Rat Lung.
abstract: BACKGROUND
  Infants born to diabetic or obese mothers are at risk of respiratory distress and persistent pulmonary hypertension of the newborn (PPHN), conceivably through fuel-mediated pathogenic mechanisms. Prior research and preventative measures focus on controlling maternal hyperglycemia, but growing evidence suggests a role for additional circulating fuels including lipids. Little is known about the individual or additive effects of a maternal high-fat diet on fetal lung development.
  
  
  OBJECTIVE
  The objective of this study was to determine the effects of a maternal high-fat diet, alone and alongside late-gestation diabetes, on lung alveologenesis and vasculogenesis, as well as to ascertain if consequences persist beyond the perinatal period.
  
  
  METHODS
  A rat model was used to study lung development in offspring from control, diabetes-exposed, high-fat diet-exposed and combination-exposed pregnancies via morphometric, histologic (alveolarization and vasculogenesis) and physiologic (echocardiography, pulmonary function) analyses at birth and 3 weeks of age. Outcomes were interrogated for diet, diabetes and interaction effect using ANOVA with significance set at p≤0.05. Findings prompted additional mechanistic inquiry of key molecular pathways.
  
  
  RESULTS
  Offspring exposed to maternal diabetes or high-fat diet, alone and in combination, had smaller lungs and larger hearts at birth. High-fat diet-exposed, but not diabetes-exposed offspring, had a higher perinatal death rate and echocardiographic evidence of PPHN at birth. Alveolar mean linear intercept, septal thickness, and airspace area (D2) were not significantly different between the groups; however, markers of lung maturity were. Both diabetes-exposed and diet-exposed offspring expressed more T1α protein, a marker of type I cells. Diet-exposed newborn pups expressed less surfactant protein B and had fewer pulmonary vessels enumerated. Mechanistic inquiry revealed alterations in AKT activation, higher endothelin-1 expression, and an impaired Txnip/VEGF pathway that are important for vessel growth and migration. After 3 weeks, mortality remained highest and static lung compliance and hysteresis were lowest in combination-exposed offspring.
  
  
  CONCLUSIONS
  This study emphasizes the effects of a maternal high-fat diet, especially alongside late-gestation diabetes, on pulmonary vasculogenesis, demonstrates adverse consequences beyond the perinatal period and directs attention to mechanistic pathways of interest. Findings provide a foundation for additional investigation of preventative and therapeutic strategies aimed at decreasing pulmonary morbidity in at-risk infants.
authors: Children's Health Research Center, Sanford Research, Sioux Falls, SD, United States of America.|Department of Internal Medicine, Sanford School of Medicine-University of South Dakota, Sioux Falls, SD, United States of America.|Department of Pediatrics, Sanford School of Medicine-University of South Dakota, Sioux Falls, SD, United States of America.|Children's Health Specialty Clinic, Sanford Children's Hospital, Sioux Falls, SD, United States of America.
authors: Michelle L
authors: http://orcid.org/0000-0001-5966-669X
authors: ML
authors: Baack
authors: Children's Health Research Center, Sanford Research, Sioux Falls, SD, United States of America.
authors: Benjamin J
authors: BJ
authors: Forred
authors: Children's Health Research Center, Sanford Research, Sioux Falls, SD, United States of America.
authors: Tricia D
authors: TD
authors: Larsen
authors: Children's Health Research Center, Sanford Research, Sioux Falls, SD, United States of America.
authors: Danielle N
authors: DN
authors: Jensen
authors: Children's Health Research Center, Sanford Research, Sioux Falls, SD, United States of America.
authors: Angela L
authors: AL
authors: Wachal
authors: Department of Internal Medicine, Sanford School of Medicine-University of South Dakota, Sioux Falls, SD, United States of America.
authors: Muhammad Ali
authors: MA
authors: Khan
authors: Children's Health Research Center, Sanford Research, Sioux Falls, SD, United States of America.|Department of Pediatrics, Sanford School of Medicine-University of South Dakota, Sioux Falls, SD, United States of America.
authors: Peter F
authors: PF
authors: Vitiello
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016640:Diabetes, Gestational; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D006439:Hemodynamics; D008168:Lung / Q000098:blood supply / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology; D039382:Maternal Nutritional Physiological Phenomena; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology*; D011650:Pulmonary Alveoli / Q000473:pathology; D011651:Pulmonary Artery / Q000473:pathology; D011667:Pulmonary Veins / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley