title: 8-Oxoguanine DNA glycosylase (OGG1) deficiency increases susceptibility to obesity and metabolic dysfunction.
abstract: Oxidative damage to DNA is mainly repaired via base excision repair, a pathway that is catalyzed by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). While OGG1 has been implicated in maintaining genomic integrity and preventing tumorigenesis, we report a novel role for OGG1 in altering cellular and whole body energy homeostasis. OGG1-deficient (Ogg1(-/-)) mice have increased adiposity and hepatic steatosis following exposure to a high-fat diet (HFD), compared to wild-type (WT) animals. Ogg1(-/-) animals also have higher plasma insulin levels and impaired glucose tolerance upon HFD feeding, relative to WT counterparts. Analysis of energy expenditure revealed that HFD-fed Ogg1(-/-) mice have a higher resting VCO(2) and consequently, an increased respiratory quotient during the resting phase, indicating a preference for carbohydrate metabolism over fat oxidation in these mice. Additionally, microarray and quantitative PCR analyses revealed that key genes of fatty acid oxidation, including carnitine palmitoyl transferase-1, and the integral transcriptional co-activator Pgc-1α were significantly downregulated in Ogg1(-/-) livers. Multiple genes involved in TCA cycle metabolism were also significantly reduced in livers of Ogg1(-/-) mice. Furthermore, hepatic glycogen stores were diminished, and fasting plasma ketones were significantly reduced in Ogg1(-/-) mice. Collectively, these data indicate that OGG1 deficiency alters cellular substrate metabolism, favoring a fat sparing phenotype, that results in increased susceptibility to obesity and related pathologies in Ogg1(-/-) mice.
authors.affiliation: Department of Molecular and Medical Genetics, Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Harini
authors.initials: H
authors.lastname: Sampath
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vartanian
authors.forename: M Rick
authors.initials: MR
authors.lastname: Rollins
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Sakumi
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
authors.forename: R Stephen
authors.initials: RS
authors.lastname: Lloyd
mesh_terms: D050154:Adiposity; D000818:Animals; D045647:DNA Glycosylases / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects*; D004734:Energy Metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008055:Lipids / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress
chemical_list: D004272:DNA, Mitochondrial; D007328:Insulin; D008055:Lipids; D006003:Glycogen; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D005947:Glucose