A cannabinoid receptor 1 inverse agonist induces weight loss and reduces airway hyperresponsiveness in a mouse model of obese asthma

Most people with severe asthma have obesity. Metabolic dysfunction, often associated with obesity, is particularly associated with severe asthma. Mechanisms linking metabolic dysfunction with asthma, and whether improving metabolic function can affect asthma, are not known. The endocannabinoid system plays a significant role in metabolism; inhibition of cannabinoid receptor 1 (CB₁R) induces weight loss and improves serum lipid profiles. We used a CB₁R inverse agonist, INV-202, in a mouse model of obese asthma and investigated changes in weight, inflammation, airway reactivity, and surfactant lipids. Mice were fed low or high-fat diets (LFD, HFD), and house dust mite (HDM) extract was delivered intranasally to induce allergic airway inflammation. Mice received INV-202 by oral gavage. Airway hyperresponsiveness was measured by FlexiVent, and lung tissue cytokines were measured by ELISA. Leukocytes and lipids in the bronchoalveolar lavage fluid (BALF) were analyzed by flow cytometry and mass spectroscopy, respectively. LFD and HFD mice lost an average of 11% and 27% of their body weight, respectively. LFD mice had a 33% decrease in CCL20 in lung tissue and a 55% decrease in neutrophils in BALF. LFD and HFD mice had improvements in airway hyperresponsiveness, particularly as measured by reduced elastance. Phosphatidylglycerol in BALF increased with INV-202, which significantly correlated with compliance in LFD mice. This study supports a significant contribution of metabolic factors related to the endocannabinoid system in lung compliance and airway reactivity, in part through effects on surfactant lipid composition, and demonstrates the potential of CB₁R inverse agonists to treat obese asthma.<b>NEW & NOTEWORTHY</b> Inhibition of the cannabinoid receptor 1, through a pharmacological inverse agonist, not only induces weight loss in a mouse model of obese asthma but also reduces airway hyperresponsiveness, particularly through decreasing elastance/increasing compliance.