title: 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.
authors.affiliation: Center for Research on Occupational and Environmental Toxicology, Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, USA.
authors.forename: Harini
authors.initials: H
authors.lastname: Sampath
authors.forename: Ayesha K
authors.initials: AK
authors.lastname: Batra
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vartanian
authors.forename: J Russ
authors.initials: JR
authors.lastname: Carmical
authors.forename: Deborah
authors.initials: D
authors.lastname: Prusak
authors.forename: Irena B
authors.initials: IB
authors.lastname: King
authors.forename: Brian
authors.initials: B
authors.lastname: Lowell
authors.forename: Lauriel F
authors.initials: LF
authors.lastname: Earley
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Wood
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Marks
authors.forename: Amanda K
authors.initials: AK
authors.lastname: McCullough
authors.forename: Lloyd
authors.initials: L
authors.lastname: R Stephen
mesh_terms: D050154:Adiposity / Q000187:drug effects / Q000235:genetics; D000818:Animals; D045647:DNA Glycosylases / Q000235:genetics*; D004036:Diet, Atherogenic; D004041:Dietary Fats / Q000009:adverse effects; D005260:Female; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000453:epidemiology / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D019683:Penetrance; D010641:Phenotype; D015995:Prevalence; D054928:Validation Studies as Topic
chemical_list: D004041:Dietary Fats; D045647:DNA Glycosylases; C481347:Neil1 protein, mouse