Obese Adipocytes Induce Fibroblast-to-Myofibroblast Transition through TGF-β1 signaling: Implications in Asthma Pathogenesis

Obesity, a key risk factor for severe asthma, is associated with worsening symptoms and poor responses to conventional therapies. Recent studies have highlighted the presence of adipocytes within airway walls, which correlates positively with body mass index (BMI). However, the role of adipocytes in asthma pathogenesis remains largely unknown. This study aims to explore their potential contribution to airway fibrosis, a progressive form of the disease, through fibroblast-to-myofibroblast transition (FMT). In vitro co-culture models were developed to investigate the interactions between adipocytes (derived from patients with and without obesity) and fibroblasts (from patients with and without asthma) on FMT. Proteomic and multiplex analyses were used to identify potential mediators of adipocyte-induced FMT. Our data revealed a significant increase in fibrogenic markers, such as alpha-smooth muscle actin and vimentin, in fibroblasts co-cultured with obese (Ob) adipocytes. Notably, this transition was more pronounced in asthmatic fibroblasts compared to healthy fibroblasts. Proteomic profiling of co-cultured Ob-adipocytes and asthmatic fibroblasts identified several significantly upregulated proteins linked to the regulation of the transforming growth factor-beta (TGF-β)signalling pathway, including inhibin A, latent TGF-β binding protein 1, thrombospondin 1 , and follistatin. The role of TGF-β was further substantiated by multiplex assays, which demonstrated a significant increase in TGF-β and leptin production by Ob-adipocytes following co-culture. These findings suggest that Ob-adipocytes may promote FMT in fibroblasts, especially asthmatic fibroblasts, by activating the TGF-β signalling pathway. This highlights a potential mechanism by which obesity exacerbates asthma severity and fibrosis, providing new avenues for therapeutic intervention.