Abstract
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.
Highlights
Nuclear and mitochondrial DNA constantly face oxidative DNA damage through reaction with endogenous and exogenous oxidants. 8-Oxo-7,8-dihydroguanine (8-oxoG) is the most commonly formed oxidative DNA lesion in the cell
This pattern of regulation was not observed for other base excision repair (BER) glycosylases such as Neil-like DNA glycosylase 1 (Neil1), Neil2, or endonuclease III-like protein 1 (Nth1), but a similar early induction of gene expression was observed for Neil3 (Supplementary Figure S1)
We have previously reported that the DNA repair enzyme OGG1 plays an unex pected and novel role in the development of obesity and adiposity [31,32,36]
Summary
Nuclear and mitochondrial DNA constantly face oxidative DNA damage through reaction with endogenous and exogenous oxidants. 8-Oxo-7,8-dihydroguanine (8-oxoG) is the most commonly formed oxidative DNA lesion in the cell. Mitochondrial content and respiration were both significantly increased in adipose tissue of Ogg1Tg animals [36] Given these intriguing changes in adipose tissue of Ogg1Tg mice, we were interested in determining if the DNA repair protein OGG1 plays a cell-intrinsic role in the adipocyte, in the process of differentiation and subsequent lipid accumulation. To address this question, we used adipocytes in culture to delineate the function of OGG1 in the adipocyte for the first time. Using both the well-established 3T3-L1 pre-adipocyte fibroblast cell line, as well as stromal vascular cells isolated from Ogg1Tg and Ogg1−/− mice, we report here our discovery of a novel role for OGG1 in differentiation and lipid accretion in the adipocyte
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