Adipocyte RNF20 Knockout Leads to Hyperinsulinemia via the H2Bub-H3K4me3-Slc2a4 Axis

The ubiquitin ligase RING finger 20 (RNF20) mediated the monoubiquitination of histone H2B at lysine 120 (H2Bub), an epigenetic modification known to regulate key biological processes such as fat tissue development, tumorigenesis, spermatogenesis and so on. Despite our previous findings showing that mice with adipocyte-specific deletion of Rnf20 (ASKO mice) develop hyperinsulinaemia, the underlying mechanisms remain unclear. In this study, we investigated the role of adipocyte RNF20 in maintaining systemic insulin homoeostasis in ASKO mice. Our results reveal that ASKO mice exhibit an enlarged pancreas, increased islet size and a greater number of pancreatic β-cells. Fat tissue in ASKO mice showed reduced insulin sensitivity, evidenced by diminished AKT phosphorylation under basal and insulin-stimulated conditions, alongside suppressed insulin signalling pathways. Furthermore, the decreased levels of histone modifications, including H2Bub, H3K4me3 and H3K79me3, were observed in both ASKO mice fat tissues and Rnf20-knockdown 3T3-L1 cells. Mechanistically, Rnf20 knockdown in adipocytes reduced H3K4me3 occupancy at the Slc2a4 gene locus, inhibiting GLUT4 expression and inducing adipose-specific insulin resistance. These findings establish a critical role for adipocyte RNF20 in the insulin signalling regulation via the H2Bub-H3K4me3-Slc2a4 axis, highlighting its importance in systemic glucose metabolism.