Insulin resistance is a fundamental pathogenic factor shared by various metabolic disorders[1]. While skeletal muscle accounts for 70-90% of insulin-stimulated glucose disposal, the mechanism underlying muscle insulin resistance is poorly understood. MG53, also named TRIM72, is expressed in striated muscle and implicated in cell membrane repair and cardiac ischemic pre- and post-conditioning[2-4]. Here we show that MG53 acts as an E3 ligase targeting insulin receptor (IR) and insulin receptor substrate 1 (IRS1) for ubiquitin-dependent degradation, and when upregulated, causes metabolic disorders. MG53 is markedly elevated in the skeletal muscle of insulin resistance models. After 35 weeks on high fat diet (HFD), wild type (wt) mice developed metabolic syndrome featuring obesity, hypertension, hyperglycemia and hyperinsulinemia. In contrast, MG53-difficient (mg53-/-) mice were resistant to HFD-induced metabolic disorders. Concomitantly, 35-week HFD induced significant glucose intolerance and insulin resistance in wt, but not in mg53-/-, mice. Furthermore, MG53 transgenic (mg53 TG) mice on regular chow diet developed metabolic syndrome characterized by obesity, hypertensive, hyperinsulinemia, along with severe glucose intolerance and insulin resistance at 38 weeks of age. These results indicate that upregulation of MG53 is both necessary and sufficient to cause systemic insulin resistance and metabolic syndrome. Insulin signaling involves tyrosine phosphorylation of IR and IRS1, and subsequent activation of PI3K-Akt signaling pathway[5]. Mechanistically, MG53 acts as an E3 ligase which targets IR and IRS1 for ubiquitin-dependent degradation, constituting a central mechanism controlling insulin signal strength in skeletal muscle. Specifically, in skeletal muscle from mg53 TG mice or wt mice on HFD, insulin-stimulated activation of IR, IRS1 and Akt was profoundly impaired. The suppressed insulin signaling is associated with posttranscriptional downregulation of IR and IRS1 via ubiquitin-dependent degradation. Importantly, in mg53-/- mice, HFD had no significant effect on IR and IRS1 protein abundance or insulin signaling efficiency. Taken together, we have shown, for the first time, that elevated MG53 expression is sufficient and necessary for HFD-mediated downregulation of IR and IRS1 and subsequent suppression of insulin signaling in skeletal muscle. These findings define MG53 as a novel therapeutic target for treating metabolic disorders and associated cardiovascular complications.