Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance

• Material Type: 博士論文
• Title: Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance
• Author/Editor: Nishimoto, Sachiko; Fukuda, Daiju; Higashikuni, Yasutomi; Tanaka, Kimie; Hirata, Yoichiro; Murata, Chie; Kim-Kaneyama, Joo-ri; Sato, Fukiko; Bando, Masahiro; Yagi, Shusuke; Soeki, Takeshi; Hayashi, Tetsuya; Imoto, Issei; Sakaue, Hiroshi; Shimabukuro, Michio; Sata, Masataka
• Author Heading: Nishimoto, Sachiko; Fukuda, Daiju; Higashikuni, Yasutomi; Tanaka, Kimie; Hirata, Yoichiro; Murata, Chie; Kim-Kaneyama, Joo-ri; Sato, Fukiko; Bando, Masahiro; Yagi, Shusuke; Soeki, Takeshi; Hayashi, Tetsuya; Imoto, Issei; Sakaue, Hiroshi; Shimabukuro, Michio; Sata, Masataka
• Publication, Distribution, etc.: American Association for the Advancement of Science
• Publication Date: 2016-03-25
• Publication Date (W3CDTF): 2016-03-25
• Alternative Title: 肥満によって遊離する脂肪細胞由来のDNA断片が脂肪組織の炎症とインスリン抵抗性を引き起こす
• Periodical title: Science Advances
• No. or year of volume/issue: 2 3
• Volume: 2
• Issue: 3
• Pages: e1501332-
• ISSN (Periodical Title): ISSN : 2375-2548
• Degree grantor/type: 徳島大学
• Date Granted: 2017-03-23
• Dissertation Number: 甲第3088号
• Degree Type: 博士（栄養学）
• Text Language Code: eng
• Subject Heading: 肥満; インスリン抵抗性; 慢性炎症; Toll-like receptor; adipose tissue; cell-free DNA; insulin resistance; macrophage; inflammation
• Target Audience: 一般
• Note (General): Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9−/−) macrophages. Fat-fed Tlr9−/− mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9−/− mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography–determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.
• Format (IMT): application/pdf
• Access Restrictions: インターネット公開
• Rights (production): 2016 © The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
• Related Material (DOI): 10.1126/sciadv.1501332
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

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http://repo.lib.tokushima-u.ac.jp/files/public/11/110123/20170929142441659787/LID201705191025.pdf fulltext

http://repo.lib.tokushima-u.ac.jp/files/public/11/110123/20170929142441966666/LID201706261002.pdf fulltext