Fibrosis, resulting from excess extracellular matrix deposition, is a feature of adipose tissue (AT) dysfunction and obesity-related insulin resistance. However, the precise mechanisms underlying AT fibrosis in obesity remain unclear. In this study, through scRNA-seq data we discovered Fibulin7 (FBLN7), a recently identified member of fibulin family, as a promoter of AT fibrosis. The precise role of FBLN7 in AT remains unknown. We showed that the loss and gain of function of FBLN7 in pre-adipocytes inhibits and promotes, respectively, TGFβ-induced fibrogenic responses. In vivo, genetic ablation of FBLN7 in adipocyte precursors, and treatment with FBLN7-neutralizing antibody dramatically alleviated AT fibrosis-inflammation state and improved systemic metabolic health. Mechanically, FBLN7 bound to thrombospondin-1 (TSP1) through its EGF-like calcium-binding domain, activated TGFBR1/TGFβ/Smad signaling via TSP1. Furthermore, in obese humans, FBLN7 levels were upregulated in both visceral fat and systemic circulation and correlated with clinical metabolic traits. And we also revealed that variant p.V99E was associated with improved metabolic performance in humans and inhibited TSP1/TGFBR1/TGFβ/Smad axis in cells. Conclusively, our findings imply that FBLN7 produced by pre-adipocytes is a potential biomarker of AT fibrosis and may represent a therapeutic target for AT fibrosis.
H. Yu: None. J. Yan: None. C. Hu: None.
