Liver-originated small extracellular vesicles with TM4SF5 target brown adipose tissue for homeostatic glucose clearance

Transmembrane 4 L six family member 5 (TM4SF5) is involved in chronic liver disease, although its role in glucose homeostasis remains unknown. TM4SF5 deficiency caused age-dependent glucose (in)tolerance with no link to insulin sensitivity. Further, hepatic TM4SF5 binding to GLUT1 promoted glucose uptake and glycolysis. Excessive glucose repletion caused hepatocytes to secrete small extracellular vesicles (sEVs) loaded with TM4SF5 (hep-sEV(Tm4sf5)), suggesting a role for sEV(Tm4sf5) in glucose metabolism and homeostasis. Hep-sEV(Tm4sf5) were smaller than sEV(Control) and recruit proteins for efficient organ tropism. Liver-derived sEVs, via a liver-closed vein circuit (LCVC) using hepatic TM4SF5-overexpressing (Alb-Tm4sf5 TG) mice (liv-sEV(Tm4sf5)), improved glucose tolerance in Tm4sf5(-/-) KO mice and targeted brown adipose tissues (BATs), possibly allowing the clearance of blood glucose as heat independent of UCP1. Taken together, hep-sEV(Tm4sf5) might clear high extracellular glucose levels more efficiently by targeting BAT compared with hep-sEV(Control), suggesting an insulin-like role for sEV(Tm4SF5) in affecting age-related metabolic status and thus body weight (BW).