Cells sustain constant oxidative stress from both exogenous and endogenous sources. When unmitigated by antioxidant defenses, reactive oxygen species damage cellular macromolecules, including DNA. Oxidative lesions in both nuclear and mitochondrial DNA are repaired via the base excision repair (BER) pathway, initiated by DNA glycosylases. We have previously demonstrated that the BER glycosylase 8-oxoguanine DNA glycosylase (OGG1) plays a novel role in body weight maintenance and regulation of adiposity. Specifically, mice lacking OGG1 (Ogg1−/−) are prone to increased fat accumulation with age and consumption of hypercaloric diets. Conversely, transgenic animals with mitochondrially-targeted overexpression of OGG1 (Ogg1Tg) are resistant to age- and diet-induced obesity. Given these phenotypes of altered adiposity in the context of OGG1 genotype, we sought to determine if OGG1 plays a cell-intrinsic role in adipocyte maturation and lipid accumulation. Here, we report that preadipocytes from Ogg1−/− mice differentiate more efficiently and accumulate more lipids than those from wild-type animals. Conversely, OGG1 overexpression significantly blunts adipogenic differentiation and lipid accretion in both pre-adipocytes from Ogg1Tg mice, as well as in 3T3-L1 cells with adenovirus-mediated OGG1 overexpression. Mechanistically, changes in adipogenesis are accompanied by significant alterations in cellular PARylation, corresponding with OGG1 genotype. Specifically, deletion of OGG1 reduces protein PARylation, concomitant with increased adipogenic differentiation, while OGG1 overexpression significantly increases PARylation and blunts adipogenesis. Collectively, these data indicate a novel role for OGG1 in modulating adipocyte differentiation and lipid accretion. These findings have important implications to our knowledge of the fundamental process of adipocyte differentiation, as well as to our understanding of lipid-related diseases such as obesity.
8‐oxoguanine glycosylase 1 (OGG1) is a DNA glycosylase that catalyzes the excision of oxidized guanines as part of the base excision repair (BER) DNA repair pathway. While OGG1 has been studied extensively for its role in tumor prevention and neurodegeneration, recent studies have indicated a novel role for this enzyme in maintaining metabolic health. In particular, deletion of OGG1 increased propensity to diet‐ and age‐induced obesity, as well as impaired skeletal muscle dysfunction. In contrast, overexpression of human OGG1 (hOGG1) significantly protected mice from diet‐induced obesity and related metabolic sequelae. Unbiased transcriptomics studies using mice constitutively overexpression OGG1 (Ogg1‐transgenic ‐Ogg1Tg) revealed significant transcriptional changes in skeletal muscle of these mice. Among the most highly induced genes, expression of the myokine fibroblast growth factor‐21(FGF21) was elevated by 9.9 fold in RNA‐Seq analyses. qPCR analysis further confirmed these changes in skeletal muscle without any alterations in the hepatic or cardiac expression of Fgf21. Commensurate with gene expression changes, plasma FGF21 was elevated by 11.2 fold in Ogg1Tg mice relative to WT controls. Conversely, Fgf21 gene expression in skeletal muscle and plasma FGF21 levels were decreased by 25 and 29% respectively in Ogg1‐/‐ mice. Consistent with increased FGF21 activity, phosphorylation of AMPK and its target acetyl CoA carboxylase (ACC), and Ser/Thr phosphorylation of Akt were significantly increased in Ogg1Tg muscle. FGF21 is known to increase expression of PGC‐1α protein. Consistently, Ogg1Tg mice had a 1.6 fold increase in PGC‐1α protein. Given these alterations, we asked if markers of muscle health such as endurance would be altered in Ogg1Tg mice. Interestingly, Ogg1Tg mice displayed a 3.4 fold increase in running capacity, consistent with improved skeletal muscle health in these animals. This improvement in exercise capacity was evident in both young and aged mice and have important implications to the management of age‐related declines in muscle health and DNA repair capacity.
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