8-Oxoguanine DNA Glycosylase (OGG1) Deficiency Increases Susceptibility to Obesity and Metabolic Dysfunction

Harini Sampath, Vladimir Vartanian, M. Rick Rollins, Sakumi Kunihiko, Yusaku Nakabeppu, R. Stephen Lloyd

Research output: Contribution to journalArticle

56 Citations (Scopus)

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 VCO2 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.

Original languageEnglish
Article numbere51697
JournalPLoS One
Volume7
Issue number12
DOIs
Publication statusPublished - Dec 17 2012

Fingerprint

DNA Glycosylases
glycosylases
obesity
Obesity
Fats
Nutrition
mice
High Fat Diet
DNA
high fat diet
Metabolism
Liver
Animals
liver
Genes
Plasmas
Oxidation
Liver Glycogen
Carnitine
carnitine palmitoyltransferase

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

8-Oxoguanine DNA Glycosylase (OGG1) Deficiency Increases Susceptibility to Obesity and Metabolic Dysfunction. / Sampath, Harini; Vartanian, Vladimir; Rollins, M. Rick; Kunihiko, Sakumi; Nakabeppu, Yusaku; Lloyd, R. Stephen.

In: PLoS One, Vol. 7, No. 12, e51697, 17.12.2012.

Research output: Contribution to journalArticle

Sampath, Harini ; Vartanian, Vladimir ; Rollins, M. Rick ; Kunihiko, Sakumi ; Nakabeppu, Yusaku ; Lloyd, R. Stephen. / 8-Oxoguanine DNA Glycosylase (OGG1) Deficiency Increases Susceptibility to Obesity and Metabolic Dysfunction. In: PLoS One. 2012 ; Vol. 7, No. 12.
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