DNA Repair Enzyme Ogg1 Regulates Hepatic Insulin Resistance in High-Fat Diet-Fed Obese Mice

Mitochondrial DNA (mtDNA) damage has been implicated in the development of insulin resistance. The mtDNA is highly specialized and encodes for proteins essential for energy metabolism. Also, mtDNA damage heightens mitochondrial oxidative stress, which is very critical for insulin resistance. OGG1 (8-oxoguanine DNA glycosylase-1) is a DNA glycosylase mediating the first step in the base excision repair which removes 7,8-dihydro-8-oxoguanine (8-oxoG) and repairs oxidized nuclear and mitochondrial DNA. Previous studies showed that Ogg1 deficiency results in an increased susceptibility to high fat diet (HFD)-induced obesity, metabolic dysfunction and insulin resistance in mice, suggesting a crucial role of Ogg1 in glucose metabolism. In the current study, we performed a 2-hour hyperinsulinemic-euglycemic clamp to measure tissue-specific insulin sensitivity in wild type (WT) and Ogg1-/- (KO) mice after chronic feeding of low fat diet (LFD as controls) or HFD. On LFD, both WT and KO mice showed comparable body weight and insulin sensitivity. After 16 weeks of HFD, the KO mice were more obese than WT mice with significant increases in whole body fat mass. There was a strong trend of increased insulin resistance with lower glucose infusion rates and whole body glucose turnover and glycogen synthesis in HFD-fed KO mice compared to HFD-fed WT mice. Hepatic insulin action was significantly lower in the HFD-fed KO mice which was consistent with recent evidence showing Ogg1 regulation of hepatic gluconeogenesis in the fed state. This is the first evidence demonstrating that Ogg1 contributes to HFD-induced insulin resistance in liver. Our findings suggest that protecting mtDNA from damage might be crucial to prevent insulin resistance and further identify therapeutic strategies for stimulating OGG1 as potential treatment of insulin resistance.