Increased airway reactivity and hyperinsulinemia in obese mice are linked by ERK signaling in brain stem cholinergic neurons.

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-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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 11 Issue 6 Pg. 934-943 (May 12 2015) ISSN: 2211-1247 [Electronic] United States
• PMID: 25937275 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Insulin
• Methacholine Chloride
• Phosphatidylinositol 3-Kinases
• Receptor, Insulin
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Brain Stem (enzymology)
• Bronchial Hyperreactivity (complications, enzymology, physiopathology)
• Bronchoconstriction
• Cholinergic Neurons (enzymology, pathology)
• Diet, High-Fat
• Enzyme Activation
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Hyperinsulinism (complications, enzymology, physiopathology)
• Inflammation (pathology)
• Injections, Intraventricular
• Insulin (metabolism)
• MAP Kinase Signaling System
• Methacholine Chloride
• Mice, Inbred C57BL
• Mice, Obese
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Receptor, Insulin (metabolism)