ID 110149
Author
Nishimoto, Sachiko Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School
Fukuda, Daiju Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Higasikuni, Yasutomi Department of Cardiovascular Medicine, The University of Tokyo
Tanaka, Kimie Division for Health Service Promotion, The University of Tokyo
Hirata, Yoichiro Department of Pediatrics, The University of Tokyo Hospital
Murata, Chie Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School
Kim-Kaneyama, Joo-ri Department of Biochemistry, Showa University School of Medicine
Sato, Fukiko Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School
Bando, Masahiro Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School
Yagi, Shusuke Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Soeki, Takeshi Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Hayashi, Tetsuya Laboratory of Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences
Imoto, Issei Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Sakaue, Hiroshi Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Shimabukuro, Michio Department of Cardio-Diabetes Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School|Diabetes and Lifestyle-Related Disease Center, Tomishiro Central Hospital
Sata, Masataka Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Keywords
cell-free DNA
inflammation
adipose tissue
insulin resistance
macrophage
Toll-like receptor-9
Content Type
Journal Article
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
Volume
2
Issue
3
Start Page
e1501332
Sort Key
1501332
Published Date
2016-03-25
Remark
Copyright: 2016 © The Authors, some rights reserved;exclusive licensee American Association forthe Advancement of Science. Distributedunder a Creative Commons AttributionNonCommercial License 4.0 (CC BY-NC).
EDB ID
Published Source
Science Advances (2016) Vol.2 No.3 e1501332
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
Publisher
departments
Medical Sciences