Insulinresistance is a fundamental pathogenic factor present in various metabolicdisorders including obesity and type 2 diabetes. Although skeletal muscle accounts for 70-90% of insulin-stimulated glucose disposal, the mechanism underlying muscle insulinresistance is poorly understood. Here we show in mice that muscle-specific mitsugumin 53 (MG53; also called TRIM72) mediates the degradation of the insulinreceptor and insulin receptor substrate 1 (IRS1), and when upregulated, causes metabolic syndrome featuring insulinresistance, obesity, hypertension and dyslipidaemia. MG53 expression is markedly elevated in models of insulinresistance, and MG53 overexpression suffices to trigger muscle insulinresistance and metabolic syndrome sequentially. Conversely, ablation of MG53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, IRS1 and insulin signalling integrity. Mechanistically, MG53 acts as an E3ligase targeting the insulin receptor and IRS1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. These findings define MG53 as a novel therapeutic target for treating metabolicdisorders and associated cardiovascular complications.

Song RS, Peng W, Zhang Y, Lv FX, Wu HK, Guo JJ, Cao YX, Pi YB, Zhang X, Jin L, Zhang M, Jiang P, Liu FH, Meng SS, Zhang XQ, Cao CM*, Xiao RP*. (2013) Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders. Nature, 494(7437):375-379.