Variable penetrance of metabolic phenotypes and development of high-fat diet-induced adiposity in NEIL1-deficient mice

Abstract

Exposure to chronic and acute oxidative stress is correlated with many human diseases, including, but not limited to, 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. We previously described the development of spontaneous late-onset obesity, hepatic steatosis, hyperinsulinemia, and hyperleptinemia in mice that are deficient in the DNA glycosylase nei-like 1 (NEIL1), which initiates base excision repair of several oxidatively damaged bases. In the current study, we report that exposure to a chronic oxidative stress in the form of a high-fat diet greatly accelerates the development of obesity in neil1(-/-) mice. Following a 5-wk high-fat diet challenge, neil1(-/-) mice gained significantly more body weight than neil1(+/+) littermates and had increased body fat accumulation and moderate to severe hepatic steatosis. Analysis of oxygen consumption by indirect calorimetry indicated a modest reduction in total oxygen consumption in neil1(-/-) mice that was abolished upon correction for lean body mass. Additionally, hepatic expression of several inflammatory genes was significantly upregulated in neil1(-/-) mice following high-fat diet challenge compared with chow-fed or neil1(+/+) counterparts. A long-term high-fat diet also induced glucose intolerance as well as a significant reduction in mitochondrial DNA and protein 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 cellular oxidative stress in neil1(-/-) mice.

NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice

“…Animals. Construction and characterization of Neil1 knockout mice was previously described (31,32). The Neil1 genotype has been backcrossed >15 generations onto a C57Bl/6J background.…”

“…Sterically, this adduct also represents the largest DNA base modification reported as a substrate for any DNA glycosylase. To extend the in vitro biochemical analyses to an in vivo repair assay, DNA adduct levels were measured in the livers of newborn WT and Neil1 −/− mice (31,32). We hypothesized that levels of AFB 1 -Fapy-dG would be significantly lower in WT vs. Neil1 −/− mice because the WT mice could repair these adducts via both the NER and BER pathways, whereas the Neil1 −/− mice would only repair this lesion via NER.…”

Oxidative DNA damage in disease—Insights gained from base excision repair glycosylase‐deficient mouse models

“…One of the most striking findings in multiple models of BER deficiency, primarily due to its unexpected nature, is that of an increased propensity to the development of obesity and metabolic syndrome in the absence of specific BER glycosylases [Vartanian et al, 2006;Sampath et al, 2011Sampath et al, , 2012b. While mice deficient in the BER glycosylases NEIL1 and OGG1 were initially developed to determine the role of BER in tumorigenesis, they were unexpectedly found to be prone to altered metabolic homeostasis.…”

“…Subsequent studies in the NEIL1-deficient model indicated that these mice were prone to increased weight gain, fat accumulation, and glucose intolerance when exposed to a high-fat diet [Sampath et al, 2011]. This increased propensity to weight gain in Neil1 2/2 mice was a consequence of increased mtDNA damage, reduced mitochondrial content, and a reduction in whole body resting energy expenditure [Vartanian et al, 2006;Sampath et al, 2011]. Following the reports of obesity and metabolic disease in a NEIL1-deficient model, mice deficient for OGG1 were also reported to be prone to obesity and metabolic syndrome, relative to wild-type (WT) counterparts [Arai et al, 2006;Sampath et al, 2012b].…”

Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities

“…Reduction or deficiency in DNA repair/replication enzyme activity is well documented to increase vulnerability for the development of cancer, neurodegenerative diseases, and aging (2). In addition, defective DNA repair enzymes are associated with the metabolic symptom; for example, DNA glycosylase (Neil1)-and OGG1-deficient mice are obese (3)(4)(5), and nucleotide excision repair protein ERCC1-XPF deficiency causes lipodystrophy (6). Furthermore, DNA damage response protein ataxia telangiectasia mutated (ATM) suppresses JNK activity through p53 signaling and mediates an antioxidant action that has been suggested to be relevant to the metabolic syndrome (7).…”