Hepatic epidermal growth factor receptor (EGFR) expression and activation are decreased during steatosis in humans and several animal models of obesity. Restoring EGFR activation in obesity-induced endoplasmic reticulum (ER) stress and diabetes is a potential therapy to improve liver function in type 2 diabetes (T2D). Mitogen-inducible gene 6 (Mig6) is an inducible feedback inhibitor of EGFR activity and, therefore, a target for enhancing EGFR signaling during diet-induced obesity and T2D. We previously observed that liver Mig6 expression was increased during obesity-induced insulin resistance in C57Bl/6J mice fed a high fat diet and by both pharmacological- and fatty acid-driven ER stress in hepatocytes, leading to decreased EGF-mediated EGFR activation. To test the hypothesis of Mig6 as a target to treat insulin resistance in T2D, we examined liver-specific Mig6 knockout mice (LKO) and their littermate controls (CON) during diet-induced obesity. We identified enhanced whole-body glucose tolerance and hepatic insulin action in LKO compared to CON mice. Moreover, liver ballooning, an oxidative stress marker, was also improved in LKO mice. Using whole transcriptome sequencing, we sought to determine the molecular mechanisms leading to liver function improvement in obesity-induced insulin resistance in LKO mice. We identified that gene expression and protein accumulation of key enzymes of both peroxisomal (e.g., Acox1, Ehhadh) and mitochondrial (e.g., Cpt2, Acadl) beta-oxidation were decreased by Mig6 ablation. This observation correlated with a compromised gene expression of liver gluconeogenic enzymes.

In conclusion, we posit that hepatic Mig6 deficiency partially reverts the effects of obesity-induced 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. A.J. Lutkewitte: None. P.T. Fueger: None.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.