TY - JOUR T1 - Loss of adipocyte identity through synergistic repression of PPARγ by TGF-β and mechanical stress JF - bioRxiv DO - 10.1101/604231 SP - 604231 AU - Ewa Bielczyk-Maczyńska AU - Brooks Taylor AU - Cayla M Miller AU - Michael L Zhao AU - Arnav Shah AU - Zahra Bahrami-Nejad AU - Alexander R Dunn AU - Mary N Teruel Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/04/11/604231.abstract N2 - Adipocytes convert into myofibroblasts in a TGF-β-dependent mouse model of fibrosis. The molecular steps and timing underlying this conversion are poorly understood, hindering development of antifibrotic therapies. Here we used two single-cell approaches, lineage tracing and live-cell imaging of an adipocyte marker PPARγ, to track the fate of adipocytes induced to convert by TGF-β. We found that TGF-β alone was not sufficient to activate the TGF-β pathway and to induce myofibroblast conversion in cells with high PPARγ expression. However, robust conversion was observed when an additional PPARγ-inhibiting stimulus, mechanical stress applied by increasing adhesion area on a stiff matrix, was applied simultaneously with TGF-β. We show that the PPARγ downregulation in response to increased adhesion area required both fibronectin and a sufficiently stiff extracellular matrix (ECM) and was partially mediated by Rho. Our results show for the first time the order of the molecular processes driving fat tissue fibrosis and the requirement for signal convergence for the loss of adipocyte identity. ER -