Maternal High-Fat Diet Programs Development of Airway Hyperinnervation and Hyperresponsiveness In Offspring Independent of Genetic Background

Abstract

HYPOTHESIS/RATIONALE: Asthma is more likely to occur in children born to obese mothers. However, understanding the mechanisms behind this increased risk has lacked genetically representative animal models. We have shown, in one mouse strain (FVB/NJ), that offspring of dams on a high-fat diet have airway hyperreactivity, airway hyperinnervation and obesity as adults. Here we test whether these pathologies are present in immature offspring of dams on high-fat diet or develop with adulthood, using diverse outbred (DO) mice. We hypothesize that offspring born to dams given a high-fat diet will develop airway hyperinnervation and resulting airway hyperresponsiveness independent of genetic background. Methods: Six-week female DO mice were fed either a 45% fat (high-fat diet; HFD) or 14% fat diet (regular diet; RD) for 8 weeks before breeding, during pregnancy, and during lactation. After weaning, all offspring were fed a regular diet. Bronchoconstriction to inhaled 5-HT (1-100mM) was measured in anesthetized, paralyzed, and mechanically ventilated offspring before and after vagotomy at 8, 12, and 16 weeks of age. Traches of offspring were collected at 4, 8, 12, and 16 weeks, fixed with Zamboni’s and labeled with PGP9.5 antibody to identify nerves. Tracheas were optical cleared, airway nerves imaged using confocal microscopy, and 3D modeled using IMARIS software. DATA/RESULTS: At birth offspring born to dams on a HFD were normal weight. However, by 4 weeks of age, these offspring had a higher % body fat and significantly increased body weight. By 12 weeks of age offspring born to dams on a HFD also had significantly increased fasting insulin and glucose accompanied by insulin resistance. At 12 weeks, offspring of dams on a HFD had increased airway epithelial sensory nerve innervation that was significantly increased at 16 weeks. Importantly, 16 week old offspring born to dams on a HFD had also developed significantly increased airway bronchoconstriction to inhaled 5-HT compared to offspring of dams on a RD. Notably, increased bronchoconstriction in offspring of HFD dams was blocked by bilateral vagotomy, indicating it was mediated by airway nerves (5-HT is known to induce bronchoconstriction via a reflex). SUMMARY OF RESULTS: 16 week old offspring born to dams fed a HFD were obese, hyperinsulinemic, hyperglycemic, had increased airway sensory nerve innervation, and airway hyperresponsiveness to 5HT. Airway hyperresponsiveness was blocked by vagotomy indicating that airway nerves mediate this process. CONCLUSION: Independent of genetic background, maternal high-fat diet significantly impacts development of airway hyperinnervation in offspring leading to airway hyperresponsiveness, mediated by airway nerves, in adult offspring (16 weeks). Development of airway hyperresponsiveness is preceded by airway hyperinnervation, increased fasting insulin and glucose, and increase body weight and fat compared to offspring of dams on a regular diet. NIH, Ruth L Kirschstein T32 Training Grant- 1T32GM142619-01. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.