Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities
| Autor: | Robert A. Harris, Kai Ming Chou, Zafer Hatahet, Yih Wen Chen |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Blood Glucose
Male Senescence medicine.medical_specialty Xeroderma pigmentosum Genotype DNA damage DNA polymerase Adipose tissue DNA-Directed DNA Polymerase Proinflammatory cytokine Mice chemistry.chemical_compound 3T3-L1 Cells Internal medicine Adipocyte Adipocytes medicine Hyperinsulinemia Animals Benzothiazoles Cellular Senescence Metabolic Syndrome Mice Knockout Multidisciplinary biology Macrophages medicine.disease Immunohistochemistry Gene Expression Regulation Neoplastic Endocrinology Adipose Tissue PNAS Plus chemistry Biochemistry biology.protein Comet Assay Insulin Resistance Reactive Oxygen Species Neoplasm Transplantation DNA Damage Toluene |
| Zdroj: | Proceedings of the National Academy of Sciences. 112 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1506954112 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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