Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities

Yih Wen Chen, Robert A. Harris, Zafer Hatahet, Kai Ming Chou

Research output: Contribution to journalArticle

15 Scopus citations

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 ç 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 upregulation 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, p16Ink4a, 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.

Original languageEnglish (US)
Pages (from-to)E4556-E4564
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number33
DOIs
StatePublished - Aug 18 2015

All Science Journal Classification (ASJC) codes

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