Fibrosis, resulting from excess extracellular matrix\u00a0(ECM)\u00a0deposition, 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\u00a0that closely associated with ECM function.<\/p>\n
Within this subset, we discerned a notable upregulation in the expression of Fibulin-7 (FBLN7), a secreted glycoprotein<\/a>, in obese mice. Similarly, in humans, FBLN7 levels exhibited an increase in visceral fat among obese individuals and demonstrated a correlation with\u00a0clinical metabolic traits. Functional studies further revealed that, in response to caloric excess, ASPCs-specific FBLN7\u00a0knockout mice display\u00a0a diminished\u00a0state\u00a0of AT fibrosis-inflammation<\/a>, along with improved systemic metabolic health. Notably, the depletion of FBLN7 in ASPCs suppressed TGF-\u03b2-induced fibrogenic responses, whereas its overexpression amplified such responses.<\/p>\n 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\u00a0conversion of latent TGF-\u03b2 to its bio-active form, subsequently promoting TGFBR1\/Smad signaling pathways. Furthermore,\u00a0we 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.<\/p>\n Source:<\/p>\n Journal reference:<\/p>\n