Circulating plasma fibronectin affects normal adipose tissue insulin sensitivity and adipocyte differentiation

Abstract Plasma fibronectin (pFN), a liver-derived, circulating protein, has been shown to affect adipocyte morphology, adipogenesis, and insulin signalling in preadipocytes in vitro . In this study, we show via injections of fluorescence-labelled pFN to mice in vivo its abundant accrual visceral and subcutaneous adipose tissues (VAT and SAT). Diet-induced obesity model of liver-specific conditional Fn1 knockout (pFN KO), showed no altered weight gain or differences, whole-body fat mass or SAT or VAT volumes after 20- week HFD-feeding, however, mice showed significantly improved glucose clearance and whole-body insulin sensitivity on normal diet. Furthermore, in vivo insulin sensitivity assay revealed significant increase in AKT phosphorylation in pFN KO SAT on normal diet as well as in normal and obese VAT of the pFN KO. Histological assessment of the pFN KO depots showed significant increase in small adipocytes on normal diet, which was particularly prominent in SAT. RNA sequencing of the normal diet-fed pFN versus control SAT revealed alterations in fatty acid metabolism and thermogenesis suggesting presence of beige adipocytes. VAT RNA sequencing after HFD showed alternations in genes reflecting stem cell populations. Our data suggests that the absence of pFN alters cell pools in AT favoring cells with increased insulin sensitivity.