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 Jr.,
Edson Antunes,
Milton A. Martins,
Mario J.A. Saad
Affiliations
Luiz O.S. Leiria
Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-887, Brazil
Fernanda M. Arantes-Costa
Department of Medicine, School of Medicine, University of São Paulo, São Paulo, SP 01246-904, Brazil
Marina C. Calixto
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-881, Brazil
Eduardo C. Alexandre
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-881, Brazil
Rodrigo F. Moura
Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-887, Brazil
Franco Folli
Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-887, Brazil
Carla M. Prado
Department of Biological Science, Federal University of São Paulo, Diadema, SP 09972-270, Brazil
Marco Antonio Prado
Robarts Research Institute, Department of Anatomy & Cell Biology and Department of Physiology and Pharmacology, University of Western Ontario, London, ON 5015, Canada
Vania F. Prado
Robarts Research Institute, Department of Anatomy & Cell Biology and Department of Physiology and Pharmacology, University of Western Ontario, London, ON 5015, Canada
Licio A. Velloso
Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-887, Brazil
José Donato Jr.
Department of Physiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil
Edson Antunes
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-881, Brazil
Milton A. Martins
Department of Medicine, School of Medicine, University of São Paulo, São Paulo, SP 01246-904, Brazil
Mario J.A. Saad
Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-887, Brazil
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-TH2 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 KDHOM−/−), 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.
