An Adipo-Pulmonary Axis Mediated by FABP4 Hormone Defines a Therapeutic Target Against Obesity-Induced Airway Disease

Abstract

Obesity-related airway disease is a clinical condition without a clear description and effective treatment. Here, we define this pathology and its unique properties, which differ from classic asthma phenotypes, and identify a novel adipo-pulmonary axis mediated by FABP4 hormone as a critical mediator of obesity-induced airway disease. Through detailed analysis of murine models and human samples, we elucidate the dysregulated lipid metabolism and immunometabolic responses within obese lungs, particularly highlighting the stress response activation and downregulation of surfactant-related genes, notably SftpC. We demonstrate that FABP4 deficiency mitigates these alterations, demonstrating a key role in obesity-induced airway disease pathogenesis. Importantly, we identify adipose tissue as the source of FABP4 hormone in the bronchoalveolar space and describe strong regulation in the context of human obesity, particularly among women. Finally, our exploration of antibody-mediated targeting of circulating FABP4 unveils a novel therapeutic avenue, addressing a pressing unmet need in managing obesity-related airway disease. These findings not only define the presence of a critical adipo-pulmonary endocrine link but also present FABP4 as a therapeutic target for managing this unique airway disease that we refer to as fatty lung disease associated with obesity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=162 HEIGHT=200 SRC="FIGDIR/small/603433v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@c1449corg.highwire.dtl.DTLVardef@7f6869org.highwire.dtl.DTLVardef@9fd41corg.highwire.dtl.DTLVardef@11eb408_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryInvestigating FABP4s pivotal role in obesity-driven airway disease, this study unveils an adipo-pulmonary axis with potential therapeutic implications.