Abstract Background Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant mesenchymal differentiation patterns contributing to progressive lung remodeling. Adipose metaplasia has been histologically reported but remains poorly characterized. We hypothesized that intra-pulmonary adipose tissue actively contributes to fibrogenesis through intercellular crosstalk mechanisms. Methods We examined lung samples from 43 IPF patients and 48 controls to quantify prevalence, topography, and morphological features of pulmonary adipose deposits. Primary lung adipocytes were cultured from IPF explants (n = 5), and conditioned media were generated to assess effects on fibroblast differentiation, migration, and proliferation. Bulk RNA sequencing identified potential mediators and pathways, validated by qPCR and functional assays. Results Intra-pulmonary adipose deposits were highly prevalent in IPF (86% vs 0% in controls, p 0. 001), with mean lung adiposity of 21. 1%, localized predominantly in subpleural fibrotic regions. Patients with higher adiposity (4th quartile) exhibited significantly more severe disease: FVC 47% vs 59% predicted (p = 0. 047), TLC 51% vs 59% predicted (p = 0. 039), and PaO2 50 vs 65 mmHg (p = 0. 027). Adiposity was independent of age, BMI, or smoking history. IPF lung adipocytes showed distinct morphology compared to hilar adipocytes with smaller size, rounder shape, and significantly higher FABP4 expression. Adipose deposits exhibited rich immune cell infiltration with abundant CD45+ leukocytes, enrichment in CD163+ M2-like macrophages, and notable T- and B-cell populations. Increased dysmorphic lymphatic vessel density (LYVE1+) was observed in fibrotic areas with adipose deposits. Functionally, adipose tissue strongly increased fibroblast proliferation (30-fold for control, 10-fold for IPF fibroblasts, p 0. 01) and induced a pro-inflammatory signature with marked upregulation of IL6, CXCL1, CXCL6, CXCL8, CCL2, and CCL7. Both adipose tissue explants and primary lung adipocytes inhibited myofibroblastic collagen production, partially via adiponectin receptor signaling. Transcriptomic analysis of primary lung adipocytes revealed upregulation of CTRP3 (adiponectin paralogue, 10. 3-16. 8 ng/mL in adipose tissue explant conditioned medium), WNT antagonists (FRZB, RSPO1), TGF-β modulators (DCN, NOG, CHRD), and PDGF ligands (PDGFC, PDGFD). Recombinant CTRP3 recapitulated the collagen inhibition effect, while siRNA-mediated knockdown of ADIPOR1/2 partially reversed this effect (47% reversion, p = 0. 12). Primary lung adipocyte-conditioned medium enhanced fibroblast migration through PDGF receptor signaling (completely abolished by CP-673451 inhibitor). Gene Set Enrichment Analysis of adipose tissue-treated fibroblasts revealed partial induction of a lipofibroblast signature (NES=2. 1, p = 6. 9e-7), with TCF21 and PLIN2 upregulation confirmed in control fibroblasts co-cultured with lung adipocytes. Conclusions Intra-pulmonary adipose tissue promotes a dedifferentiated, proliferative, migratory, and pro-inflammatory fibroblast phenotype with partial lipofibroblast characteristics while inhibiting terminal myofibroblast differentiation, creating a microenvironment favoring chronic remodeling in IPF. This abstract is funded by: This study was supported by the France 2030 program through the IdEx InFibrex Université Paris Cité (ANR 18 IDEX 0001), by ANR PRC “WATIPF” grant (ANR-25-CE17-6639-01) and by a generous donation from Philippe Hellmann’s family, from Danielle and Yves Lebesgue, and from the F Iniciativas company (Frédéric Bouté).
Husseini et al. (Fri,) studied this question.