Consequences of a Maternal High-Fat Diet and Late Gestation Diabetes on the Developing Rat Lung

Abstract

RationaleInfants 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.ObjectiveThe 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.MethodsA 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.ResultsOffspring 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.ConclusionThis 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.

Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways that Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts

“…Methods and model characteristics of the four animal groups used in this study have been detailed previously [29,30]. Brie y, young adult female rats received either control or HF diet (Teklad, Harlan Laboratories, Madison, WI) for at least 28 days before mating and throughout pregnancy.…”

“…Insulin and c-peptide levels were measured on 25ul of newborn (P1) serum using the MILLIPLEX Map Rat Metabolic panel (MilliporeSigma, Burlington, MA) as previously done [26,29] and Total Protein kinase B isoform 2 (AKT2) and Ser473-phosphorylated AKT2 (regulatory site for insulin signaling) were measured using the MILLIPLEX Map Phospho/Total AKT2 2-plex Magnetic Bead Panel (MilliporeSigma, Burlington, MA) according to manufacturer's protocol as described [29]. Brie y, 15ug of aforementioned newborn (P1) rat heart protein was incubated overnight with antibody coated beads.…”

Preterm birth in women with diabetes mellitus

“…гестации [4,[25][26][27]. В экспериментальных моделях СД на крысах и кроликах показано, что у плодов на фоне гипергликемии в легких уменьшается количество альвеолоцитов II типа [28], снижается синтез фосфатидилхолина [29] и экспрессия сурфактантных белков [30]. Неадекватный гликемический контроль во время беременности ассоциирован также с низким уровнем фосфолипидов в амниотической жидкости [31,32] и более поздним созреванием легких плода [34,35].…”

Unravelling the impact of early life exposures on lung structure and function in the developmental origins of asthma

“…Unfortunately, to date, there has been a scarcity of research investigating how these early life risk factors alter normal lung development and how these alterations may lead to mechanical abnormalities that limit normal lung function and promote lung disease including asthma. One study in rats suggests that a maternal high‐fat diet and gestational diabetes alter lung compliance, pulmonary vasculogenesis and pulmonary surfactant secretion, and promote persistent pulmonary hypertension in the offspring . The primary lung defects appeared to be driven by a loss of surfactant and surfactant‐producing cells within the lung of the offspring.…”

“…One study in rats suggests that a maternal high-fat diet and gestational diabetes alter lung compliance, pulmonary vasculogenesis and pulmonary surfactant secretion, and promote persistent pulmonary hypertension in the offspring. 7 The primary lung defects appeared to be driven by a loss of surfactant and surfactant-producing cells within the lung of the offspring. Their initial investigations suggest that these effects may be driven through impairment of the Txnip/VEGF pathway.…”