Adipose tissue fibrosis is driven by an overabundance of extracellular matrix, a hallmark of tissue dysfunction linked to obesity-related insulin resistance. New findings point to adipogenic stem and precursor cells (ASPCs) as a key source of these ECM proteins and as potential initiators of fibrosis in fat tissue. Using single-cell RNA sequencing, researchers uncovered a distinct ASPC subset that is tightly tied to ECM-related activities.
Within this subset, Fibulin-7 (FBLN7), a secreted glycoprotein, showed a marked increase in expression in obese mice. In humans, FBLN7 levels rose in visceral fat among individuals with obesity and correlated with clinical metabolic traits. Functional experiments demonstrated that when ASPCs are challenged with excess calories, mice with ASPC-specific deletion of FBLN7 exhibited a reduced fibrotic and inflammatory state in adipose tissue, accompanied by overall improvements in systemic metabolic health. Conversely, removing FBLN7 dampened TGF-β–driven fibrogenic responses, while boosting FBLN7 amplified them.
Mechanistically, FBLN7 binds to thrombospondin-1 (TSP1) through its EGF-like calcium-binding domain, stabilizing TSP1 protein. This stabilization facilitates the activation of latent TGF-β, thereby engaging TGFBR1/Smad signaling pathways that drive fibrosis. In addition, researchers generated an anti-FBLN7 neutralizing antibody, which significantly alleviated diet-induced adipose tissue fibrosis. Collectively, these findings position FBLN7 produced by ASPCs as a major regulator of adipose tissue fibrosis and highlight FBLN7 as a promising target for therapeutic intervention in obesity-associated metabolic dysfunction.
