Deficiency of the DNA glycosylase OGG1 predisposes mice to metabolic disease

Abstract

Exposure to oxidative stress can result in damage to DNA bases, especially to mitochondrial DNA, and is correlated with numerous human diseases. The 8‐oxoguanine DNA glycosylase, OGG1, initiates base excision repair of 8‐OH‐dG, the most common oxidative DNA lesion, and is implicated in the prevention of cancer and neurodegeneration. Here, we report a novel role for this DNA repair enzyme in the maintenance of metabolic homeostasis. Mice deficient in OGG1 (Ogg1−/−) show an increased propensity to adiposity and hepatic lipid accumulation, compared to wild‐type counterparts, when exposed to an oxidative stress in the form of a 10‐week long high‐fat diet (HFD). Glucose tolerance is significantly impaired in HFD‐fed Ogg1−/− animals, despite increased plasma insulin levels. While food intake and voluntary activity appear unchanged in Ogg1−/− mice, indirect calorimetry measurements reveal a slight increase in day‐time RER, suggesting a preference for carbohydrates as a fuel source in HFD‐fed Ogg1−/− mice. Microarray analyses of hepatic gene expression reveal a shift towards glycolysis over TCA cycle metabolism and fatty acid oxidation in Ogg1−/− mice. Collectively, these data indicate that OGG1 deficiency results in an increased susceptibility to obesity, potentially by altering mitochondrial integrity and substrate preference. Support: AHA 11POST7480004 to HS, NIH RO1 DK075974 to RSL