An adipo-pulmonary axis mediated by FABP4 hormone defines a target against obesity-induced airway disease

The non-Th2 asthma including obesity-related asthma is a therapeutic challenge. Nearly 60% of the patients with severe asthma in the US are obese and they do not adequately respond to conventional treatments and have a more severe progression. Hence, understanding disease mechanisms and designing new therapeutics are of utmost importance and represent a critical unmet need. The FABP4 (fatty acid-binding protein) is a fundamental immunometabolic regulator in obesity-related diseases. We recently identified FABP4 as a hormone, regulated in obesity with pleiotropic effects on metabolic organs. We present exciting data showing the detection of FABP4 in the bronchoalveolar lavage fluid (BAL) and regulation in obesity, identifying FABP4 as a potential novel adipo-pulmonary mediator, that could be therapeutically targeted. Through adipose tissue transplantation and luciferase tagged FABP4 expressing 3T3-L1 adipocyte implantation and adipose-tissue specific deletion studies we showed that the source of the FABP4 protein in the airways is the adipose tissue. Most importantly, FABP4 deficiency or a-FABP4 mAb treatment resulted in significant attenuation of obesity-induced airway hyperresponsiveness. Furthermore, we generated mechanistic insights into obese lung pathologies via performing single-cell RNAseq experiments from whole lungs of lean vs obese WT vs FABP4 deficient mice, showing that obesity induces stress response and primes the lungs for multiple pathologies including asthma. We concluded that in obesity, an increase in FABP4 from the adipose tissue integrates metabolic status with lung biology and creates an exciting potential therapeutic target for a substantial unmet need.