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ID 110123
Title Alternative
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
Author
Nishimoto, Sachiko Tokushima University
Higashikuni, Yasutomi The University of Tokyo
Tanaka, Kimie The University of Tokyo
Hirata, Yoichiro The University of Tokyo
Kim-Kaneyama, Joo-ri Showa University
Sato, Fukiko Tokushima University
Bando, Masahiro Tokushima University
Hayashi, Tetsuya Osaka University
Shimabukuro, Michio Tokushima University|Tomishiro Central Hospital KAKEN Search Researchers
Keywords
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
Content Type
Thesis or Dissertation
Description
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.
Journal Title
Science Advances
ISSN
23752548
Publisher
American Association for the Advancement of Science
Volume
2
Issue
3
Start Page
e1501332
Published Date
2016-03-25
Remark
内容要旨・審査要旨・論文本文の公開:
内容要旨・審査要旨:LID201705191025.pdf
論文本文:LID201706261002.pdf
著者の申請により要約(2017-05-19公開)に替えて論文本文を公開(2017-06-26)
本論文は, 著者Sachiko Nishimotoの学位論文として提出され, 学位審査・授与の対象となっている。
Rights
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).
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3088号
Diploma Number
甲栄第240号
Granted Date
2017-03-23
Degree Name
Doctor of Nutritional Science
Grantor
Tokushima University
departments
Medical Sciences