Increased airway reactivity and hyperinsulinemia in obese mice are linked by ERK signaling in brain stem cholinergic neurons.
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 KD(HOM-/-)), 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.
Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-887, Brazil.
Luiz O S
LOS
Leiria
Department of Medicine, School of Medicine, University of São Paulo, São Paulo, SP 01246-904, Brazil.
Fernanda M
FM
Arantes-Costa
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-881, Brazil.
Marina C
MC
Calixto
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-881, Brazil.
Eduardo C
EC
Alexandre
Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-887, Brazil; Obesity and Comorbidities Research Center (O.C.R.C.), State University of Campinas, Campinas, SP 13083-887, Brazil.
Rodrigo F
RF
Moura
Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-887, Brazil; Obesity and Comorbidities Research Center (O.C.R.C.), State University of Campinas, Campinas, SP 13083-887, Brazil; Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, TX 78229-3900, USA.
Franco
F
Folli
Department of Biological Science, Federal University of São Paulo, Diadema, SP 09972-270, Brazil.
Carla M
CM
Prado
Robarts Research Institute, Department of Anatomy & Cell Biology and Department of Physiology and Pharmacology, University of Western Ontario, London, ON 5015, Canada.
Marco Antonio
MA
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
VF
Prado
Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-887, Brazil; Obesity and Comorbidities Research Center (O.C.R.C.), State University of Campinas, Campinas, SP 13083-887, Brazil.
Licio A
LA
Velloso
Department of Physiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil.
José
J
Donato
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-881, Brazil.
Edson
E
Antunes
Department of Medicine, School of Medicine, University of São Paulo, São Paulo, SP 01246-904, Brazil.
Milton A
MA
Martins
Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP 13083-887, Brazil; Obesity and Comorbidities Research Center (O.C.R.C.), State University of Campinas, Campinas, SP 13083-887, Brazil. Electronic address: msaad@fcm.unicamp.br.
Mario J A
MJA
Saad
D000818:Animals; D001933:Brain Stem / Q000201:enzymology*; D016535:Bronchial Hyperreactivity / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D016084:Bronchoconstriction; D059329:Cholinergic Neurons / Q000201:enzymology* / Q000473:pathology; D059305:Diet, High-Fat; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006946:Hyperinsulinism / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D007249:Inflammation / Q000473:pathology; D007276:Injections, Intraventricular; D007328:Insulin / Q000378:metabolism; D020935:MAP Kinase Signaling System; D016210:Methacholine Chloride; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism
D007328:Insulin; D016210:Methacholine Chloride; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D048049:Extracellular Signal-Regulated MAP Kinases