Hepatic epidermal growth factor receptor (EGFR) expression and activation are decreased during steatosis in humans and animal models of obesity. Restoring EGFR activation in obesity-induced endoplasmic reticulum (ER) stress and diabetes is a potential therapy to improve liver function and metabolism in type 2 diabetes (T2D) . Mitogen-inducible gene 6 (Mig6) is an inducible feedback inhibitor of EGFR activity; we previously observed that liver Mig6 expression was increased during obesity-induced insulin resistance in mice and by both pharmacological- and fatty acid-driven ER stress in hepatocytes, leading to decreased EGF-mediated EGFR activation. To test Mig6 as a potential target to treat insulin resistance in T2D, we examined liver-specific Mig6 knockout mice (LKO) and their littermate controls (CON) . LKO mice exhibited reduced liver fat content and normalized glycogen storage with diet-induced obesity. In addition, we observed enhanced hepatic insulin action and whole-body glucose tolerance, due to increased hepatic glucose uptake, as determined by hyperinsulinemic-euglycemic clamps. Using whole transcriptome sequencing, peroxisomal and mitochondrial beta-oxidation genes were decreased by Mig6 ablation, correlating with a compromised gene expression of liver gluconeogenic enzymes. Moreover, analysis of mice aged for one year, a different physiological insult causing insulin resistance and liver oxidative stress, we were able to recapitulate the main findings as with diet-induced obesity: decreased gluconeogenesis, enhanced liver glucose uptake leading to increased glucose tolerance. Moreover, in aged LKO mice, liver oxidative stress markers were reduced. In conclusion, we postulate that hepatic Mig6 deficiency partially reverts the effects of diabetes by decreasing hepatic glucose output and reducing cellular oxidative stress, thereby establishing Mig6 as a therapeutic candidate for treating insulin resistance in obesity and T2D.
J. M. Irimia-dominguez: None. E. A. Bloom-saldana: None. P. T. Fueger: Consultant; Protomer Technologies.