TY - JOUR T1 - Obesity-induced senescent macrophages activate a fibrotic transcriptional program in adipocyte progenitors JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202101286 VL - 5 IS - 5 SP - e202101286 AU - Nabil Rabhi AU - Kathleen Desevin AU - Anna C Belkina AU - Andrew Tilston-Lunel AU - Xaralabos Varelas AU - Matthew D Layne AU - Stephen R Farmer Y1 - 2022/05/01 UR - https://www.life-science-alliance.org/content/5/5/e202101286.abstract N2 - Adipose tissue fibrosis is regulated by the chronic and progressive metabolic imbalance caused by differences in caloric intake and energy expenditure. By exploring the cellular heterogeneity within fibrotic adipose tissue, we demonstrate that early adipocyte progenitor cells expressing both platelet-derived growth factor receptor (PDGFR) α and β are the major contributors to extracellular matrix deposition. We show that the fibrotic program is promoted by senescent macrophages. These macrophages were enriched in the fibrotic stroma and exhibit a distinct expression profile. Furthermore, we demonstrate that these cells display a blunted phagocytotic capacity and acquire a senescence-associated secretory phenotype. Finally, we determined that osteopontin, which was expressed by senescent macrophages in the fibrotic environment promoted progenitor cell proliferation, fibrotic gene expression, and inhibited adipogenesis. Our work reveals that obesity promotes macrophage senescence and provides a conceptual framework for the discovery of rational therapeutic targets for metabolic and inflammatory disease associated with obesity. ER -