Intra-pulmonary adipocytes exert a profibrotic effect

<bold>Background:</bold> Ectopic adipose tissue was recently identified in patients with idiopathic pulmonary fibrosis (IPF). We aimed to investigate the effects of adipose tissue on lung fibroblast phenotype and identify implicated mediators. <bold>Methods:</bold> Fresh tissue was obtained from IPF explanted lungs at our institution. Fatty deposits were resected, fragmented, and used to generate adipose explant conditioned medium (expCM) and isolate lung adipose stromal fraction (ASF) (containing preadipocytes) which was amplified and cryopreserved. ASF was differentiated into mature adipocytes to generate CM (adipoCM). CM was used at 1:4 v/v to stimulate lung fibroblasts from IPF and control patients. We evaluated myofibroblast differentiation markers (protein/mRNA), migration assays and proliferation/metabolic assays (cyQuant/WST8). ASF ±differentiated into adipocytes were analysed using bulk RNAseq to identify potential mediators. <bold>Results:</bold> Transcriptomic analysis of ASF (n=4) identified multiple ligands and mediators, among which ADIPOR ligands. AdipoCM (n=8) decreased expression of Col1a1 at baseline and in presence of TGFb1 (p<0.001) in control and IPF lung fibroblasts and decreased expression of aSMA in presence of TGFb1 in control fibroblasts (p<0.05). ExpCM (n=4) showed similar results. SiRNA inhibition of ADIPOR1/2 dampened the inhibitory effect of adipoCM. Both adipoCM and expCM exhibited a proliferative effect and a strong pro-migratory effect and on control and IPF lung fibroblasts, which was dampened by PDGFR small inhibitor. <bold>Conclusions:</bold> Intra-pulmonary adipocytes prompt lung fibroblasts to adopt an undifferentiated, proliferative and migratory phenotype. These effects are partially mediated through the ADIPOR and PDGF signalling pathways.