title: Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities.
abstract: Obesity and the metabolic syndrome have evolved to be major health issues throughout the world. Whether loss of genome integrity contributes to this epidemic is an open question. DNA polymerase η (pol η), encoded by the xeroderma pigmentosum (XP-V) gene, plays an essential role in preventing cutaneous cancer caused by UV radiation-induced DNA damage. Herein, we demonstrate that pol η deficiency in mice (pol η(-/-)) causes obesity with visceral fat accumulation, hepatic steatosis, hyperleptinemia, hyperinsulinemia, and glucose intolerance. In comparison to WT mice, adipose tissue from pol η(-/-) mice exhibits increased DNA damage and a greater DNA damage response, indicated by up-regulation and/or phosphorylation of ataxia telangiectasia mutated (ATM), phosphorylated H2AX (γH2AX), and poly[ADP-ribose] polymerase 1 (PARP-1). Concomitantly, increased cellular senescence in the adipose tissue from pol η(-/-) mice was observed and measured by up-regulation of senescence markers, including p53, p16(Ink4a), p21, senescence-associated (SA) β-gal activity, and SA secretion of proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) as early as 4 wk of age. Treatment of pol η(-/-) mice with a p53 inhibitor, pifithrin-α, reduced adipocyte senescence and attenuated the metabolic abnormalities. Furthermore, elevation of adipocyte DNA damage with a high-fat diet or sodium arsenite exacerbated adipocyte senescence and metabolic abnormalities in pol η(-/-) mice. In contrast, reduction of adipose DNA damage with N-acetylcysteine or metformin ameliorated cellular senescence and metabolic abnormalities. These studies indicate that elevated DNA damage is a root cause of adipocyte senescence, which plays a determining role in the development of obesity and insulin resistance.
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Yih-Wen
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Richard Roudebush Veterans Affairs Medical Center and the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Biological and Physical Sciences, Northwestern State University of Louisiana, Natchitoches, LA 71497.
authors.forename: Zafer
authors.initials: Z
authors.lastname: Hatahet
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202; kmchou3@gmail.com.
authors.forename: Kai-ming
authors.initials: KM
authors.lastname: Chou
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology; D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry; D001786:Blood Glucose / Q000378:metabolism; D016922:Cellular Senescence; D020552:Comet Assay; D004249:DNA Damage; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D007150:Immunohistochemistry; D007333:Insulin Resistance; D008264:Macrophages / Q000166:cytology; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D017382:Reactive Oxygen Species / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives / Q000737:chemistry; D000099270:Y-Family DNA Polymerases
chemical_list: D052160:Benzothiazoles; D001786:Blood Glucose; D004259:DNA-Directed DNA Polymerase; D017382:Reactive Oxygen Species; D014050:Toluene; C121565:pifithrin; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases
keywords: DNA damage; DNA polymerase η; adipose tissue; obesity; senescence