Increased Airway Reactivity and Hyperinsulinemia in Obese Mice Are Linked by ERK Signaling in Brain Stem Cholinergic Neurons

Luiz O S Leiria, Fernanda M. Arantes-Costa, Marina C. Calixto, Eduardo C. Alexandre, Rodrigo F. Moura, Franco Folli, Carla M. Prado, Marco Antonio Prado, Vania F. Prado, Licio A. Velloso, José Donato, Edson Antunes, Milton A. Martins, Mario J A Saad

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12 Scopus citations

Abstract

Obesity is a major risk factor for asthma, which is characterized by airway hyperreactivity (AHR). In obesity-associated asthma, AHR may be regulated by non-T<inf>H</inf>2 mechanisms. We hypothesized that airway reactivity is regulated by insulin in the CNS, and that the high levels of insulin associated with obesity contribute to AHR. We found that intracerebroventricular (ICV)-injected insulin increases airway reactivity in wild-type, but not in vesicle acetylcholine transporter knockdown (VAChT KD<sup>HOM-/-</sup>), mice. Either neutralization of central insulin or inhibition of extracellular signal-regulated kinases (ERK) normalized airway reactivity in hyperinsulinemic obese mice. These effects were mediated by insulin in cholinergic nerves located at the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (NA), which convey parasympathetic outflow to the lungs. We propose that increased insulin-induced activation of ERK in parasympathetic pre-ganglionic nerves contributes to AHR in obese mice, suggesting a drug-treatable link between obesity and asthma.

Original languageEnglish (US)
Pages (from-to)934-943
Number of pages10
JournalCell Reports
Volume11
Issue number6
DOIs
Publication statusPublished - May 12 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Leiria, L. O. S., Arantes-Costa, F. M., Calixto, M. C., Alexandre, E. C., Moura, R. F., Folli, F., ... Saad, M. J. A. (2015). Increased Airway Reactivity and Hyperinsulinemia in Obese Mice Are Linked by ERK Signaling in Brain Stem Cholinergic Neurons. Cell Reports, 11(6), 934-943. https://doi.org/10.1016/j.celrep.2015.04.012