PMID- 27051864 OWN - NLM STAT- MEDLINE DCOM- 20170504 LR - 20220311 IS - 2375-2548 (Electronic) IS - 2375-2548 (Linking) VI - 2 IP - 3 DP - 2016 Mar TI - Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance. PG - e1501332 LID - 10.1126/sciadv.1501332 [doi] LID - e1501332 AB - 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. FAU - Nishimoto, Sachiko AU - Nishimoto S AD - Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. FAU - Fukuda, Daiju AU - Fukuda D AD - Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. FAU - Higashikuni, Yasutomi AU - Higashikuni Y AD - Department of Cardiovascular Medicine, The University of Tokyo, Tokyo 113-8655, Japan. FAU - Tanaka, Kimie AU - Tanaka K AD - Division for Health Service Promotion, The University of Tokyo, Tokyo 113-8655, Japan. FAU - Hirata, Yoichiro AU - Hirata Y AUID- ORCID: 0000-0002-6837-6819 AD - Department of Pediatrics, The University of Tokyo Hospital, Tokyo 113-8655, Japan. FAU - Murata, Chie AU - Murata C AD - Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. FAU - Kim-Kaneyama, Joo-Ri AU - Kim-Kaneyama JR AD - Department of Biochemistry, Showa University School of Medicine, Tokyo 142-8555, Japan. FAU - Sato, Fukiko AU - Sato F AD - Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. FAU - Bando, Masahiro AU - Bando M AD - Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. FAU - Yagi, Shusuke AU - Yagi S AD - Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. FAU - Soeki, Takeshi AU - Soeki T AD - Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. FAU - Hayashi, Tetsuya AU - Hayashi T AD - Laboratory of Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan. FAU - Imoto, Issei AU - Imoto I AD - Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. FAU - Sakaue, Hiroshi AU - Sakaue H AD - Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. FAU - Shimabukuro, Michio AU - Shimabukuro M AD - 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. FAU - Sata, Masataka AU - Sata M AD - Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160325 PL - United States TA - Sci Adv JT - Science advances JID - 101653440 RN - 0 (Toll-Like Receptor 9) RN - 9007-49-2 (DNA) SB - IM MH - Adipocytes/drug effects/*metabolism MH - Adipose Tissue/drug effects/*metabolism MH - Adult MH - Aged MH - Animals MH - Bone Marrow/metabolism/pathology MH - Cell Communication MH - DNA/blood/*metabolism MH - Female MH - Gene Deletion MH - Gene Expression MH - Humans MH - Insulin Resistance/genetics MH - Macrophages/metabolism MH - Male MH - Mice MH - Mice, Knockout MH - Middle Aged MH - Obesity/genetics/*metabolism/pathology MH - Panniculitis/genetics/*metabolism/pathology MH - Signal Transduction MH - Toll-Like Receptor 9/antagonists & inhibitors/genetics/metabolism PMC - PMC4820373 OTO - NOTNLM OT - Toll-like receptor-9 OT - adipose tissue OT - cell-free DNA OT - inflammation OT - insulin resistance OT - macrophage EDAT- 2016/04/07 06:00 MHDA- 2017/05/05 06:00 PMCR- 2016/03/25 CRDT- 2016/04/07 06:00 PHST- 2015/09/25 00:00 [received] PHST- 2016/02/11 00:00 [accepted] PHST- 2016/04/07 06:00 [entrez] PHST- 2016/04/07 06:00 [pubmed] PHST- 2017/05/05 06:00 [medline] PHST- 2016/03/25 00:00 [pmc-release] AID - 1501332 [pii] AID - 10.1126/sciadv.1501332 [doi] PST - epublish SO - Sci Adv. 2016 Mar 25;2(3):e1501332. doi: 10.1126/sciadv.1501332. eCollection 2016 Mar.