1. A Novel Role for the DNA Repair Enzyme 8-Oxoguanine DNA Glycosylase in Adipogenesis
- Author
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Agnieszka Dobrzyn, Harini Sampath, Hong Ye, Sai Santosh Babu Komakula, and Bhavya Blaze
- Subjects
Mitochondrial DNA ,obesity ,DNA Repair ,DNA repair ,Transgene ,medicine.disease_cause ,base excision repair ,Catalysis ,Article ,DNA Glycosylases ,lcsh:Chemistry ,Inorganic Chemistry ,chemistry.chemical_compound ,Mice ,Adipocyte ,3T3-L1 Cells ,medicine ,Adipocytes ,Animals ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,adipocyte differentiation ,Adipogenesis ,Organic Chemistry ,lipid accretion ,Cell Differentiation ,General Medicine ,Base excision repair ,Lipid Metabolism ,Computer Science Applications ,Cell biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,Gene Expression Regulation ,DNA glycosylase ,Reactive Oxygen Species ,Oxidative stress - 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&minus, /&minus, ) 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&minus, 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.
- Published
- 2021