TY - JOUR
T1 - A novel role for the DNA repair enzyme 8-oxoguanine DNA glycosylase in adipogenesis
AU - Komakula, Sai Santosh Babu
AU - Blaze, Bhavya
AU - Ye, Hong
AU - Dobrzyn, Agnieszka
AU - Sampath, Harini
N1 - Funding Information:
This work was supported by NIH DK100640 to H.S., a grant from European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska Curie COFUND grant agreement no. 665735 (Bio4Med) to A.D. and H.S., and by funding from the Polish Ministry of Science and Higher Education as part of 2016-2020 funds for the implementation of international projects (agreement no. 548/H2020/COFUND/2016/2) to A.D. and H.S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank Dawn Brasaemle (Rutgers University) for invaluable assistance with adenoviral purifications, and Anupom Mondal and Natalie Burchat (Rutgers University) for useful discussions. We would also like to thank R. Stephen Lloyd (Oregon Health & Science University) for the gift of purified OGG1 protein, Lyudmila Rachek (U. of South Alabama) for the gift of the MTS-hOgg1a and control plasmids, and Lars Eide (U. of Oslo) for the original gift of Ogg1Tg animals. This work was supported by NIH grant DK100640 to HS, a grant from European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska Curie COFUND grant agreement no. 665735 (Bio4Med) to AD and HS, and by funding from the Polish Ministry of Science and Higher Education as part of 2016-2020 funds for the implementation of international projects (agreement no. 548/H2020/COFUND/2016/2) to AD and HS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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 -/- 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.
AB - 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 -/- 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.
KW - Adipocyte differentiation
KW - Base excision repair
KW - Dna repair
KW - Lipid accretion
KW - Obesity
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U2 - 10.3390/ijms22031152
DO - 10.3390/ijms22031152
M3 - Article
C2 - 33503804
AN - SCOPUS:85099933235
SN - 1661-6596
VL - 22
SP - 1
EP - 14
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 3
M1 - 1152
ER -