Paracrine Signaling by Distinct Adipose Tissue Depots Regulate Fibroblast Mechanobiology and Functional Heterogeneity.

PURPOSE: Adipose tissues have long been recognized for their diverse endocrine functions that serve to regulate tissue homeostasis. Although adipose depot-specific secretory profiles can differentially regulate fibroblast fate and fibrotic tissue remodeling, systematic investigation of how adipose depots of varying phenotypes influence fibroblast mechanobiology remains lacking. METHODS: By integrating secretome profiling with functional and mechanobiological assays in a controlled adipose-fibroblast coculture platform, we mechanistically investigate how canonical brown (BAT), white (WAT), and beige adipose tissues (thoracic and abdominal perivascular adipose tissue; T-PVAT and A-PVAT, respectively) govern fibroblast-to-myofibroblast transition (FMT) through depot-specific paracrine signaling. RESULTS: Thermogenic depots (BAT and T-PVAT) enhance fibroblast proliferation, collagen deposition, and stiffness (1.9-fold increase in single cell modulus; p < 0.0001) alongside specific adipokines that regulate metabolism (ANGPTL3, FGF1) and inhibit calcification (Fetuin A). In contrast, lipid-storing depots (WAT and A-PVAT) promote fibroblast migration (79% scratch wound closure at 12 h; p < 0.01) and matrix degradation through upregulated pro-inflammatory cytokines (CCL2, IL-6) and fibrogenic mediators (PAI-1, TIMP-1). Mechanistically, BAT and T-PVAT secretomes induce pro-contractile and matrix-producing fibroblast phenotypes, while A-PVAT and WAT promote migratory and matrix-remodeling behaviors. Further, T-PVAT uniquely combines BAT-like genetic identity with elevated RAGE-DPP4 signaling, resulting in excessive fibroblast activation, stiffening, and collagen production that can be attenuated via pharmacological inhibition of DPP4. CONCLUSIONS: Our findings establish adipose depots as distinct modulators of fibroblast phenotype, wherein depot-specific mediators promote mechanobiological alterations that balance reparative and pathological remodeling processes related to fibrosis. Differential biological responses by fibroblasts exposed to diverse adipose phenotypes underscores the potential for adipose-driven stromal crosstalk to mitigate fibrotic remodeling alongside metabolic and cardiovascular disease comorbidities. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12195-025-00864-z.