Deleting Insulin Receptors on Advillin-Expressing Cells Prevents Airway Hyperresponsiveness in Offspring of Obese Mice

RATIONALE: Children born to obese mothers are more likely to develop asthma. In mice, maternal obesity induces hyperinsulinemia and obesity in offspring even when the offspring are fed a normal diet. These offspring have airway hyperresponsiveness mediated by a marked increase in airway sensory nerves, an effect that happens after the mice develop high insulin. Here we test whether blocking insulin signaling in sensory neurons, most of which express advillin, can prevent airway hyperresponsiveness in adult offspring of obese dams. Methods: We used an Advillin-Cre ERT2 mice in which a tamoxifen inducible cre recombinase is driven by the promoter for advillin, which is expressed by most sensory neurons. These mice were crossed with mice with floxed insulin receptors to create an Advillin Insulin receptor knockout mouse (AIRKO). Six-week-old female AIRKO mice were fed a 45% high-fat diet (HFD) or a 14% regular diet (RD) for 8 weeks before breeding and throughout pregnancy and lactation. After weaning, all offspring were fed a regular diet. At 8 weeks of age, some offspring were treated with tamoxifen (100 mg/kg, i.p. 5 consecutive days) to knockout insulin receptors in advillin positive neurons. At 16 weeks, airway response to inhaled 5-hydroxytryptamine (5-HT) (1-100 mM, 10 ul) was measured in anesthetized, paralyzed, and mechanically ventilated offspring before and after vagotomy. Results: When insulin receptors were intact, offspring of obese dams had increased bronchoconstriction to inhaled 5-HT compared to offspring born to lean dams. Deleting insulin receptors on advillin-positive neurons prevented this hyperresponsiveness. 5-HT induced bronchoconstriction was blocked by bilateral vagotomy, confirming it is mediated by airway nerves. Conclusion: Deleting insulin receptors in advillin-expressing neurons prevents airway-nerve mediated hyperresponsiveness in offspring of obese dams. Thus, avoiding hyperinsulinemia is a potential therapeutic strategy to prevent asthma in children born to obese mothers. NIH HL164474 (Nie) NIH HL163087 (Nie) NIH T32GM142619-01 (Williams) NIH T32-5T32HL083808-14 (Williams) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.