Fibulin-7 in progenitor cells promotes adipose tissue fibrosis and disrupts metabolic homeostasis in obesity [RNA-seq]

Fibrosis, resulting from excess extracellular matrix deposition, is a feature of adipose tissue (AT) dysfunction and obesity-related insulin resistance. In this study, through a comparative analysis of single-cell RNA-sequencing data from stromal vascular cells in the AT of lean and obese mice, we identify Fibulin-7 (FBLN7), a newly recognized member of the fibulin family of secreted glycoproteins, as a promoter of fibrosis. Moreover, we found that FBLN7 levels are upregulated in visceral fat among obese individuals, showing a correlation with clinical metabolic traits. However, the precise role of FBLN7 in AT and the underlying regulatory mechanisms remain to be elucidated. Here, we demonstrate that loss and overexpression of FBLN7 in adipogenic stem and precursor cells (ASPCs) inhibits and promotes, respectively, TGF-ß-induced fibrogenic responses. In vivo, in response to caloric excess, ASPCs-specific FBLN7 knockout mice display a diminished state of AT fibrosis-inflammation state, coupled with improved systemic metabolic health. Mechanistically, FBLN7 binds to thrombospondin-1 (TSP1) via its EGF-like calcium-binding domain, enhancing TSP1 protein stability. This interaction, in turn, facilitates the conversion of latent TGF-ß to its bio-active form, thereby promoting TGFBR1/Smad signaling. Furthermore, we develop an anti-FBLN7 neutralizing antibody, which could dramatically alleviate diet-induced AT fibrosis. Conclusively, our findings imply that FBLN7 produced by ASPCs exerts a major influence in AT fibrosis and may represent a potential target for therapeutic intervention. Overall design: RNA-seq on WT ASPCs infected with lentiviral sh-FBLN7 versus those infected with sh-Ctrl after TGF-ß1 stimulation