Polarity Protein AF6 Controls Hepatic Glucose Homeostasis and Insulin Sensitivity by Modulating IRS1/AKT Insulin Pathway in an SHP2-Dependent Manner

Insulin resistance is a major contributing factor in the development of metabolic disease. Although numerous functions of the polarity protein AF6 (afadin and MLLT4) have been identified, a direct effect on insulin sensitivity has not been previously described. We show that AF6 is elevated in the liver tissues of dietary and genetic mouse models of diabetes. We generated liver-specific AF6 knockout mice and show that these animals exhibit enhanced insulin sensitivity and liver glycogen storage, whereas overexpression of AF6 in wild-type mice by adenovirus-expressing AF6 led to the opposite phenotype. Similar observations were obtained from in vitro studies. In addition, we discovered that AF6 directly regulates IRS1/AKT kinase-mediated insulin signaling through its interaction with Src homology 2 domain-containing phosphatase 2 (SHP2) and its regulation of SHP2’s tyrosine phosphatase activity. Finally, we show that knockdown of hepatic AF6 ameliorates hyperglycemia and insulin resistance in high-fat diet–fed or db/db diabetic mice. These results demonstrate a novel function for hepatic AF6 in the regulation of insulin sensitivity, providing important insights about the metabolic role of AF6.