title: Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance.
abstract: 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.
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Nishimoto
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Daiju
authors.initials: D
authors.lastname: Fukuda
authors.affiliation: Department of Cardiovascular Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Yasutomi
authors.initials: Y
authors.lastname: Higashikuni
authors.affiliation: Division for Health Service Promotion, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Kimie
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Pediatrics, The University of Tokyo Hospital, Tokyo 113-8655, Japan.
authors.forename: Yoichiro
authors.identifier: 0000-0002-6837-6819
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Murata
authors.affiliation: Department of Biochemistry, Showa University School of Medicine, Tokyo 142-8555, Japan.
authors.forename: Joo-Ri
authors.initials: JR
authors.lastname: Kim-Kaneyama
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Fukiko
authors.initials: F
authors.lastname: Sato
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Bando
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Shusuke
authors.initials: S
authors.lastname: Yagi
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Soeki
authors.affiliation: Laboratory of Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Imoto
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakaue
authors.affiliation: Department of Cardio-Diabetes Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.; Diabetes and Lifestyle-Related Disease Center, Tomishiro Central Hospital, Okinawa 901-0243, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Shimabukuro
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication; D004247:DNA / Q000097:blood / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015434:Panniculitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D051217:Toll-Like Receptor 9; D004247:DNA
keywords: Toll-like receptor-9; adipose tissue; cell-free DNA; inflammation; insulin resistance; macrophage