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Ablation of XP-V Gene Causes Adipose Tissue Senescence and Metabolic Abnormalities

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Ablation of XP-V Gene Causes Adipose Tissue Senescence and Metabolic Abnormalities Ablation of XP-V gene causes adipose tissue PNAS PLUS senescence and metabolic abnormalities Yih-Wen Chena, Robert A. Harrisb, Zafer Hatahetc, and Kai-ming Choua,1 aDepartment of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202; bRichard Roudebush Veterans Affairs Medical Center and the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; and cDepartment of Biological and Physical Sciences, Northwestern State University of Louisiana, Natchitoches, LA 71497 Edited by James E. Cleaver, University of California, San Francisco, CA, and approved June 26, 2015 (received for review April 12, 2015) Obesity and the metabolic syndrome have evolved to be major DNA polymerase η (pol η) is a specialized lesion bypass poly- health issues throughout the world. Whether loss of genome merase that faithfully replicates across UV-induced cyclobutane integrity contributes to this epidemic is an open question. DNA pyrimidine dimers (9) to rescue stalled DNA replication forks polymerase η (pol η), encoded by the xeroderma pigmentosum from potential breakages and mutations. Defects in the gene (XP-V) gene, plays an essential role in preventing cutaneous cancer encoding pol η produce a variant form of the autosomal recessive caused by UV radiation-induced DNA damage. Herein, we demon- disease xeroderma pigmentosum (XP-V) (9). Patients with XP-V strate that pol η deficiency in mice (pol η−/−) causes obesity with are highly sensitive to sunlight and prone to cutaneous cancer (9). visceral fat accumulation, hepatic steatosis, hyperleptinemia, In addition to skin, pol η is expressed in most tissues (10). The hyperinsulinemia, and glucose intolerance. In comparison to WT expression of pol η correlates with the effectiveness of anticancer − − mice, adipose tissue from pol η / mice exhibits increased DNA therapeutic agents that exert their activity by introducing DNA damage and a greater DNA damage response, indicated by up- lesions that block the progression of DNA replication (11). In regulation and/or phosphorylation of ataxia telangiectasia mu- addition to exogenous introduced DNA lesions, pol η contributes tated (ATM), phosphorylated H2AX (γH2AX), and poly[ADP-ribose] to genomic stability during unperturbed DNA replication (12) and polymerase 1 (PARP-1). Concomitantly, increased cellular senes- replicates across reactive oxygen species (ROS)-induced oxidative cence in the adipose tissue from pol η−/− mice was observed and DNA lesions 8-oxoG (7,8-dihydro-8-oxoguanine), thymine glycol, GENETICS measured by up-regulation of senescence markers, including p53, and lipid peroxidation DNA adducts generated during endoge- p16Ink4a, p21, senescence-associated (SA) β-gal activity, and SA se- nous metabolic processes (13, 14). ROS generated from endoge- cretion of proinflammatory cytokines interleukin 6 (IL-6) and tu- nous metabolism or exogenous sources has been associated with mor necrosis factor α (TNF-α) as early as 4 wk of age. Treatment of cancer, aging, and the metabolic syndrome. − − pol η / mice with a p53 inhibitor, pifithrin-α, reduced adipocyte Therefore, the initial hypothesis for our studies was that pol η senescence and attenuated the metabolic abnormalities. Further- contributes to reduce tumorigenesis by managing oxidative DNA more, elevation of adipocyte DNA damage with a high-fat diet or lesions in other organs. However, in a 2-y study, no increase in the − − sodium arsenite exacerbated adipocyte senescence and metabolic incidence of tumors of any type was found with pol η KO (pol η / ) − − − − abnormalities in pol η / mice. In contrast, reduction of adipose mice (15). Instead, we found pol η / mice develop metabolic DNA damage with N-acetylcysteine or metformin ameliorated cel- abnormalities that induce obesity. lular senescence and metabolic abnormalities. These studies indi- cate that elevated DNA damage is a root cause of adipocyte Results and Discussion senescence, which plays a determining role in the development Metabolic Abnormalities in Pol η Mice. Compared with littermate WT − − of obesity and insulin resistance. mice, pol η / mice gained more weight with age, particularly after 48 wk, with no genotype difference in food or water consumption DNA polymerase η | obesity | senescence | DNA damage | adipose tissue Significance he human genome is constantly challenged by exogenous and Tendogenous DNA damaging agents. To ensure genome in- The metabolic syndrome has evolved to be a major health issue tegrity, human cells have faithful DNA replication machinery globally. The association between genome integrity and meta- and DNA repair systems that are coordinated by DNA damage bolic abnormalities is not well understood. Our results indicate response networks. In response to different extents or types of that increased DNA damage and persistent activation of the DNA lesions, the DNA damage response activates appropriate DNA damage response induce adipocyte senescence in DNA cellular responses, including transient or permanent (senes- polymerase η knockout (pol η−/−) mice. Suppression of adipocyte cence) cell cycle arrest, or apoptosis, to minimize the detrimental senescence with a p53 inhibitor, pifithrin-α, alleviated metabolic − − effects of DNA lesions (1). Reduction or deficiency in DNA abnormalities in pol η / mice.AnincreaseordecreaseinDNA repair/replication enzyme activity is well documented to increase damage affected the senescence status of adipocytes accord- vulnerability for the development of cancer, neurodegenerative ingly, which was also in concordance with the severity of met- −/− diseases, and aging (2). In addition, defective DNA repair en- abolic abnormalities in the pol η mice. Our current results zymes are associated with the metabolic symptom; for example, indicate that reduced genome integrity plays a causative role in DNA glycosylase (Neil1)- and OGG1-deficient mice are obese provoking adipocyte senescence that leads to development of (3–5), and nucleotide excision repair protein ERCC1-XPF de- obesity and insulin resistance. ficiency causes lipodystrophy (6). Furthermore, DNA damage Author contributions: Y.-W.C., R.A.H., Z.H., and K.-m.C. designed research; Y.-W.C., Z.H., response protein ataxia telangiectasia mutated (ATM) sup- and K.-m.C. performed research; Y.-W.C., R.A.H., and K.-m.C. analyzed data; and Y.-W.C., presses JNK activity through p53 signaling and mediates an an- R.A.H., and K.-m.C. wrote the paper. tioxidant action that has been suggested to be relevant to the The authors declare no conflict of interest. metabolic syndrome (7). Nucleotide excision repair XP-A pro- This article is a PNAS Direct Submission. tein may affect metabolism by altering mitochondrial function 1To whom correspondence should be addressed. Email: [email protected]. (8). To date, the mechanisms that link genome instability and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. metabolic dysregulation have not been elucidated. 1073/pnas.1506954112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1506954112 PNAS Early Edition | 1of9 Downloaded by guest on September 27, 2021 Fig. 1. Pol η−/− mice develop metabolic abnormalities. (A) Autopsy of WT and pol η−/− mice at 4 (4W) and 72 (72W) wk of age; (B) body weight gain (n = 12); (C) body fat percentages (n = 12); (D) circulating leptin and (E) insulin levels; (F) HOMA-IR (n = 8); (G) glucose tolerance test (GTT) with area under curve (AUC) + + (n = 8); (H) liver stained with Oil Red O (Scale bars: 50 μM); (I) H&E staining of adipose macrophage infiltration; (J) F4/80 /CD11b -positive cells (n = 6) in adipocytes from mice at 72 wk (w) of age; (K) IL-6; (L) TNF-α;(M) adiponectin in plasma (n = 8); (N) H&E staining of visceral fat histological sections; (O) quantitation of adipocyte size (n = 400); and (P) expression of PPAR-γ, SREBP1-p125, and SREBP1-p68 subunits. Histological pictures and blots are repre- sentative of six independent experiments. The graphical data, which are shown as the mean ± SEM, were analyzed by the Student t test (*P < 0.05). 2of9 | www.pnas.org/cgi/doi/10.1073/pnas.1506954112 Chen et al. Downloaded by guest on September 27, 2021 (Fig. 1 A–C and Fig. S1A). Autopsies revealed increased visceral fat genes SREBP1 and PPAR-γ (18) (Fig. 1P and Fig. S2B). The PNAS PLUS − − encasing the abdominal organs of pol η / mice (Fig. 1A). By 72 wk, administration of diets high in fat or fructose promoted greater − − − − pol η / mice had gained an average of 55% more weight than WT obesity and exacerbated the metabolic abnormalities in the pol η / littermates (14.0 g vs. 9.0 g, respectively; Fig. 1B), with 37.5% more mice relative to their WT littermates (Fig. S3), which further in- − − − − body fat (38.5% vs. 28.0%, respectively; Fig. 1C). Pol η / mice also dicated that pol η / mice are prone to the development of meta- developed hyperleptinemia (Fig. 1D), hyperinsulinemia (Fig. 1E), bolic abnormalities. Together, these characteristics of obesity with higher blood glucose (Fig. S1B), higher homeostasis model assess- concomitant development of glucose intolerance and reduced − − ment of insulin resistance (HOMA-IR) (Fig. 1F), reduced energy insulin sensitivity in the pol η / mice suggest a preventive role expenditure (Fig. S1C), and reduced glucose tolerance (Fig. 1G) for pol η in the onset of metabolic abnormalities. compared with WT littermates. Hepatic steatosis was also appar- − − − − ent in the pol η / mice, as evidenced by enlarged
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