Atp10c Heterozygous Mice Represent a Genetic Model of Insulin Resistance Associated with Diet‐Induced Obesity and Altered Glucose Uptake via Both Insulin‐Dependent and Independent Pathways

Diet‐induced obesity is a major risk factor for a number of disorders including non‐insulin‐dependent type 2 diabetes mellitus. In our novel mouse model of obesity, the gene, Atp10c is a strong candidate for insulin resistance and diet‐induced obesity. As such, we hypothesized that ATP10C has a key role in glucose metabolism via insulin‐dependent and independent signaling pathways. First, we examined the expression of Atp10c in both genetic and environmental mouse models of obesity. Next, we performed Western analysis to detect potential targets of ATP10C in both phosphatidylinositol‐3‐kinase (PI3K) and mitogen‐activated protein kinase (MAPK) pathways. We saw high expression of Atp10c in both skeletal muscle and adipose depots. When accessing MAPK pathway proteins, the mutants showed a significant decrease in the ratio of activated to native forms of p38 and ERK1/2. Additionally, we observed differences in the PI3K pathway as there were significant increases in PI3K and AS160 expression. These results along with data from our investigations of skeletal muscle support our hypothesis that ATP10C has an important role in glucose metabolism, and suggest that the action of Atp10c is potentially mediated via both the MAPK pathway as well as the PI3K pathway.