Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

Abstract

Obesity is a substantial risk factor for developing asthma, but the molecular mechanisms underlying this relationship are unclear. We tested the role of insulin in airway responsiveness to nerve stimulation using rats genetically prone or resistant to diet-induced obesity. Airway response to vagus nerve stimulation and airway M 2 and M 3 muscarinic receptor function were measured in obeseprone and -resistant rats with high or low circulating insulin. The effects of insulin on nerve-mediated human airway smooth muscle contraction and human M 2 muscarinic receptor function were tested in vitro. Our data show that increased vagally mediated bronchoconstriction in obesity is associated with hyperinsulinemia and loss of inhibitory M 2 muscarinic receptor function on parasympathetic nerves. Obesity did not induce airway inflammation or increase airway wall thickness. Smooth muscle contraction to acetylcholine was not increased, indicating that hyperresponsiveness is mediated at the level of airway nerves. Reducing serum insulin with streptozotocin protected neuronal M 2 receptor function and prevented airway hyperresponsiveness to vagus nerve stimulation in obese rats. Replacing insulin restored dysfunction of neuronal M 2 receptors and airway hyperresponsiveness to vagus nerve stimulation in streptozotocintreated obese rats. Treatment with insulin caused loss of M 2 receptor function, resulting in airway hyperresponsiveness to vagus nerve stimulation in obese-resistant rats, and inhibited human neuronal M 2 receptor function in vitro. This study shows that it is not obesity per se but hyperinsulinemia accompanying obesity that potentiates vagally induced bronchoconstriction by inhibiting neuronal M 2 muscarinic receptors and increasing acetylcholine release from airway parasympathetic nerves.Keywords: hyperinsulinemia; obesity; asthma; airway responsiveness; neural M 2 muscarinic receptor Clinical RelevanceObesity-induced asthma does not respond well to traditional anti-inflammatory therapies, suggesting that it is a unique asthma phenotype. Here we show that hyperinsulinemia causes airway hyperresponsiveness to vagus nerve stimulation in obese rats. In human trachea and in rats, we demonstrate that insulin inhibits M 2 muscarinic receptors on airway parasympathetic nerves, resulting in increased acetylcholine release and increased airway contraction. Because hyperinsulinemia is greater and more prevalent in obese individuals, these data may explain why obese individuals are prone to asthma exacerbations and suggest that anticholinergic drugs may be effective in this specific phenotype of asthma.In the United States, 31% of adults and 15% of children are obese. In obese and overweight individuals, the prevalence of asthma (1-3) and the rate of new-onset asthma have increased (4-6). Obese patients with asthma also have increased severity of illness and reduced effectiveness of steroids compared with nonobese patients with asthma (1, 6, 7). The mechanisms by which obesity predisposes to asthma are unclear, limi...

Obesity and asthma: beyond TH2 inflammation

“…Conversely, a combination of fluticasone/salmeterol yielded greater improvements in asthma outcomes in comparison with montelukast over a range of BMIs [7]. Recently published experimental studies have suggested that metabolic changes induced by high-fat fed obese mice result in increased parasympathetic activity, which results in an increase of acetylcholine levels in the lungs, thus producing AHR [19,31]. These findings highlight the possible use of the antimuscarinics as adjuvant drugs in the treatment of asthma in obese subjects.…”

Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation

“…129 Insulin resistance also increases free insulin-like growth factor, which is associated with ASM proliferation. 130 Furthermore, insulin may increase airway hyperresponsiveness by modulating parasympathetic stimulation, studied in an obese 131 These studies suggest that insulin resistance and associated hyperinsulinemia influence ASM cell function through different mechanisms, with the end result of increased bronchial hyperresponsiveness. Translational studies are now needed to study the role of each of these pathways in ASM cells obtained from obese asthmatics.…”

Mechanisms of Asthma in Obesity. Pleiotropic Aspects of Obesity Produce Distinct Asthma Phenotypes

“…Data from animal models suggest that there are changes in the neurological control of airway smooth muscle tone through cholinergic signaling pathways in obesity (25)(26)(27). High insulin levels are present in some obese humans, and high insulin levels can increase vagal-induced bronchoconstriction both through peripheral effects on acetylcholine release (25) and through centrally mediated effects on vagal signaling (26). Leptin, an adipokine increased in obesity, can also affect the parasympathetic regulation of airway tone (27).…”

“…Clinical studies to date have not specifically targeted the late-onset asthma of obesity. Animal studies demonstrating that cholinergic signaling affects airway tone (25)(26)(27) suggest that focused studies targeting insulin resistance and/or cholinergic pathways in the lateonset asthma of obesity associated with little overt inflammation might be worthwhile.…”