Inhibition of Leptin Regulation of Parasympathetic Signaling as a Cause of Extreme Body Weight-Associated Asthma

Abstract

SUMMARY 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 M3 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.

Childhood asthma and obesity—what is the true link?

“…The lack of leptin signaling in the brain as a result of leptin resistance in obesity leads to increased parasympathetic signaling in airway smooth muscles in mice and subsequent bronchoconstriction. 28 This mechanism might explain why patients with obesity and asthma might be resistant to steroids as reported by Forno et al 13 who found a significant decrease in steroid efficacy in children with a higher BMI, similar to previously reported findings in the adult population. Whether these results from mice studies are applicable to humans remain to be seen and require more translational studies.…”

“…27 In another recent mice study, Arteaga-Solis et al 28 described a noninflamma-tory mechanism relevant to obese asthma from disruption of the autonomic nervous system mediated by leptin. The lack of leptin signaling in the brain as a result of leptin resistance in obesity leads to increased parasympathetic signaling in airway smooth muscles in mice and subsequent bronchoconstriction.…”

Obesity and asthma: beyond TH2 inflammation

“…Taken together, these studies have led to the general consensus that airway inflammation is not the unique and essential mechanism driving the association between obesity and asthma that it was first thought to be; the reason that corticosteroid anti-inflammatory drugs are less effective in the treatment of asthma in overweight and obese patients [5][6][7][8]19]. In accordance with those findings, a recent experimental study detected AHR in high-fat fed obese mice in an inflammation-independent manner [20], highlighting the possibility that metabolic changes induced by obesity/diabetes would mediate inflammatory-independent AHR phenotype in obese patients.…”

Endocrine regulation of airway contractility is overlooked

“…OBR (LEPR), the leptin receptor, is expressed on ASM (Nair et al 2008). However, leptin has no direct effect on ASM contraction (Nair et al 2008, Arteaga-Solis et al 2013. Leptin rather acts through the central nervous system to attenuate the constitutive muscarinic activation of ASM that emanates from the parasympathetic inputs of the vagi However, the effect of leptin in the context of asthma is not clear.…”