A Novel Role for the DNA Repair Enzyme 8-Oxoguanine DNA Glycosylase in Adipogenesis

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.

Maternal Transmission of Human OGG1 Protects Mice Against Genetically- and Diet-Induced Obesity Through Increased Tissue Mitochondrial Content

“…These data further support our working hypothesis that the improved metabolic phenotype in Ogg1 Tg mice is a consequence of increased mitochondrial content and improved function in WAT (Komakula et al, 2018). In further support of a role for OGG1 in modulating adipocyte behavior, we recently showed that OGG1 genotype corresponds with adipocyte differentiation capacity (Komakula et al, 2021). Preadipocytes lacking OGG1 differentiated faster and accumulated more lipids than WT cells, while hOGG1 expression significantly blunted adipocyte differentiation and lipid accretion.…”

“…Preadipocytes lacking OGG1 differentiated faster and accumulated more lipids than WT cells, while hOGG1 expression significantly blunted adipocyte differentiation and lipid accretion. These phenotypes in isolated preadipocytes and 3T3 cells correspond with obesity predisposition or resistance in Ogg1 – / – and Ogg1 Tg animals, respectively ( Komakula et al, 2021 ). They also indicate an important cell-intrinsic role for OGG1 in the adipocyte, as supported by our current studies.…”

The Interplay between Insulin Resistance, Inflammation, Oxidative Stress, Base Excision Repair and Metabolic Syndrome in Nonalcoholic Fatty Liver Disease

“…Preadipocytes from Ogg1 −/− mice were more differentiated and accumulated more lipids than WT mice; from Ogg1 Tg had reduced differentiation and lipid content Komakula et al, 2021 [245] Abbreviations: CPT1: carnitine palmitoyl transferase-1; ETC: electron transport chain; HFD: high-fat diet; IR: insulin resistance; MCD:methionine-choline-deficient; MPO: myeloperoxidase; mtDNA: mitochondrial DNA; ob/ob: genetically obese; PDH: pyruvate dehydrogenase; Pgc-1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; TCA: tricarboxylic acid cycle; WT: wild-type.…”

Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function

“…Around the same time, small-molecule activators of OGG1 were reported ( 4 , 5 ). Applications of these molecules for targeting OGG1 in high–oxidative stress conditions, such as Alzheimer’s disease and obesity, have been suggested ( 6 – 8 ). In the literature, prominent examples of enzyme activators exhibit their effect by allosteric control ( 9 – 12 ).…”