Inhibition of leptin regulation of parasympathetic signaling as a cause of extreme body weight-associated asthma.

Abstract

Impaired lung function caused by decreased airway diameter (bronchoconstriction) is frequently observed whether body weight is abnormally high or low. That these opposite conditions affect the airways similarly suggests that the regulation of airway diameter and body weight are intertwined. We show here that, independently of its regulation of appetite, melanocortin pathway, or sympathetic tone, leptin is necessary and sufficient to increase airway diameter by signaling through its cognate receptor in cholinergic neurons. The latter decreases parasympathetic signaling through the M(3) muscarinic receptor in airway smooth muscle cells, thereby increasing airway diameter without affecting local inflammation. Accordingly, decreasing parasympathetic tone genetically or pharmacologically corrects bronchoconstriction and normalizes lung function in obese mice regardless of bronchial inflammation. This study reveals an adipocyte-dependent regulation of bronchial diameter whose disruption contributes to the impaired lung function caused by abnormal body weight. These findings may be of use in the management of obesity-associated asthma.

• Authors: Emilio Arteaga-Solis, Tiffany Zee, Charles W Emala, Charles Vinson, Jürgen Wess, Gerard Karsenty
• Journal: Cell metabolism (Cell Metab) Vol. 17 Issue 1 Pg. 35-48 (Jan 08 2013) ISSN: 1932-7420 [Electronic] United States
• PMID: 23312282 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Cholinergic Antagonists
• Leptin
• Receptor, Muscarinic M3

Topics

• Animals
• Asthma (metabolism, physiopathology)
• Body Weight (physiology)
• Bronchi (anatomy & histology, physiopathology)
• Bronchoconstriction (drug effects)
• Cholinergic Antagonists (pharmacology)
• Cholinergic Neurons (metabolism)
• Diet, High-Fat
• Inflammation (physiopathology)
• Leptin (antagonists & inhibitors, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Myocytes, Smooth Muscle (metabolism)
• Obesity (metabolism, physiopathology)
• Parasympathetic Nervous System (metabolism)
• Receptor, Muscarinic M3 (metabolism)
• Signal Transduction