Development of high‐fat diet‐induced obesity and hepatic inflammation in NEIL1 deficient mice

Exposure to oxidative stress is correlated with many human diseases including cancer, heart disease, diabetes, and obesity. In addition to cellular lipids and proteins, cellular oxidative stress can result in damage to DNA bases, especially in mitochondrial DNA (mtDNA). Accordingly, mice deficient in the DNA repair glycosylase, NEIL1, have been reported to develop features of the metabolic syndrome. In this study, we sought to establish a role for NEIL1 in cellular and whole body resistance to oxidative stress. We report here that exposure to chronic oxidative stress in the form of a high‐fat diet greatly accelerates the development of obesity in neil1 −/− mice, relative to wild‐type counterparts. Following high‐fat feeding, neil1 −/− mice gained significantly more body weight and had increased adiposity and induction of moderate to severe hepatic steatosis. Neil1 −/− mice also had reduced oxygen consumption and increased hepatic expression of several inflammatory genes, relative to wild‐type mice. Additionally, high‐fat feeding impaired glucose tolerance and led to a significant reduction in hepatic mtDNA content in neil1 −/− mice. Collectively, these data indicate that NEIL1 deficiency results in an increased susceptibility to obesity and related complications, potentially by lowering the threshold for tolerance of oxidative stress and impairing the cell's ability to repair mtDNA damage.