Fibulin-7 in progenitor cells promotes adipose tissue fibrosis and disrupts metabolic homeostasis in obesity.

Abstract

Fibrosis, resulting from excess extracellular matrix (ECM) deposition, is a feature of adipose tissue (AT) dysfunction and obesity-related insulin resistance. Emerging evidence indicates that adipogenic stem and precursor cells (ASPCs) are a crucial origin of ECM proteins and possess the potential to induce AT fibrosis. Here, we employed single-cell RNA-seq and identified a unique subset of ASPCs that closely associated with ECM function. Within this subset, we discerned a notable upregulation in the expression of Fibulin-7 (FBLN7), a secreted glycoprotein, in obese mice. Similarly, in humans, FBLN7 levels exhibited an increase in visceral fat among obese individuals and demonstrated a correlation with clinical metabolic traits. Functional studies further revealed that, in response to caloric excess, ASPCs-specific FBLN7 knockout mice display a diminished state of AT fibrosis-inflammation, along with improved systemic metabolic health. Notably, the depletion of FBLN7 in ASPCs suppressed TGF-β-induced fibrogenic responses, whereas its overexpression amplified such responses. Mechanistically, FBLN7 interacted with thrombospondin-1 (TSP1) via its EGF-like calcium-binding domain, thereby enhancing the stability of the TSP1 protein. This, in turn, facilitated the conversion of latent TGF-β to its bio-active form, subsequently promoting TGFBR1/Smad signaling pathways. Furthermore, we developed an anti-FBLN7 neutralizing antibody, which could dramatically alleviate diet-induced AT fibrosis. These results suggest that FBLN7, produced by ASPCs, exerts a major influence in the development of AT fibrosis and may represent a potential target for therapeutic intervention.