title: 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: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors: Emilio
authors: E
authors: Arteaga-Solis
authors: Tiffany
authors: T
authors: Zee
authors: Charles W
authors: CW
authors: Emala
authors: Charles
authors: C
authors: Vinson
authors: Jürgen
authors: J
authors: Wess
authors: Gerard
authors: G
authors: Karsenty
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism* / Q000503:physiopathology; D001835:Body Weight / Q000502:physiology; D001980:Bronchi / Q000033:anatomy & histology / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects; D018680:Cholinergic Antagonists / Q000494:pharmacology; D059329:Cholinergic Neurons / Q000378:metabolism; D059305:Diet, High-Fat; D007249:Inflammation / Q000503:physiopathology; D020738:Leptin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D010275:Parasympathetic Nervous System / Q000378:metabolism*; D043587:Receptor, Muscarinic M3 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018680:Cholinergic Antagonists; D020738:Leptin; D043587:Receptor, Muscarinic M3