Abstract
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.
Highlights
White adipose tissue (WAT) exhibits remarkable plasticity and plays a central role in regulating systemic energy homeostasis
Deletion of Trem2 in bone marrow cells led to deterioration of the metabolic outcomes in obese mice. It is currently unknown whether macrophage functional heterogeneity contributes to WAT fibrosis and how these cells communicate with adipocyte progenitor cell differentiation pathways
To identify cellular changes occurring in the fibrotic WAT stroma, we applied single-cell RNA sequencing to the stromal fraction isolated from epididymal WAT of C57BL/6J male mice fed either low-fat diet (LFD) or high-fat diet (HFD) starting at 6 wk of age for 24 wk
Summary
White adipose tissue (WAT) exhibits remarkable plasticity and plays a central role in regulating systemic energy homeostasis. In response to obesity various stromal-vascular cells (SVCs) including progenitor and immune cells undergo numerical and functional changes leading to WAT fibrosis and inflammation, thereby exacerbating metabolic dysfunction (Sun et al, 2011, 2013). Macrophages are the most abundant leukocyte in WAT of both mice and humans and contribute to insulin resistance during obesity by promoting a proinflammatory phenotype (Wynn et al, 2013) They aggregate in WAT to form crown-like structures (CLSs) and adopt a metabolically activated phenotype to eliminate dead adipocytes (Murano et al, 2008). Deletion of Trem in bone marrow cells led to deterioration of the metabolic outcomes in obese mice It is currently unknown whether macrophage functional heterogeneity contributes to WAT fibrosis and how these cells communicate with adipocyte progenitor cell differentiation pathways. Our studies identified new mechanisms that may explain the impaired immune function in the obese patient and obesity-associated metabolic disorders and inflammatory pathologies
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