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Consequences of a Maternal High-Fat Diet and Late Gestation Diabetes on the Developing Rat Lung
Michelle L Baack1,2,3,4, Benjamin J Forred1, Tricia D Larsen1
1Children's Health Research Center, Sanford Research, Sioux Falls, SD, United States of America.
Insights
Maternal high-fat diet significantly impacts fetal lung development, increasing risks for respiratory issues like persistent pulmonary hypertension of the newborn (PPHN). These adverse effects persist beyond birth, highlighting the need for preventative strategies.
Area of Science:
- Developmental Biology
- Perinatal Medicine
- Cardiovascular Physiology
Background:
- Infants of diabetic or obese mothers face risks of respiratory distress and PPHN, potentially due to fuel-mediated mechanisms.
- While maternal hyperglycemia is a focus, lipids also play a role, yet maternal high-fat diet effects on fetal lung development are unclear.
Purpose of the Study:
- To investigate the impact of maternal high-fat diet, with and without diabetes, on fetal lung alveologenesis and vasculogenesis.
- To determine if these pulmonary effects extend beyond the perinatal period.
Main Methods:
- A rat model assessed lung development in offspring from control, diabetes, high-fat diet, and combined exposure groups.
- Analyses included morphometrics, histology, echocardiography, and pulmonary function at birth and 3 weeks.
- ANOVA was used to analyze diet, diabetes, and interaction effects, with mechanistic studies for molecular pathways.
Main Results:
- Maternal diabetes or high-fat diet led to smaller lungs and larger hearts in offspring at birth.
- High-fat diet exposure increased perinatal mortality and showed PPHN indicators.
- Reduced surfactant protein B and fewer pulmonary vessels were observed in diet-exposed newborns, with altered molecular pathways (AKT, endothelin-1, Txnip/VEGF).
- Long-term, combination-exposed offspring had highest mortality and poorest lung compliance.
Conclusions:
- Maternal high-fat diet, particularly with diabetes, significantly affects pulmonary vasculogenesis with lasting adverse outcomes.
- Mechanistic pathways involved in vessel growth and migration are implicated.
- Findings support further research into preventative and therapeutic strategies for pulmonary morbidity in at-risk infants.
Rationale:
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.
Conclusion:
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.
