The Radioprotective 105/MD-1 Complex Contributes to Diet-Induced Obesity and Adipose Tissue Inflammation
- Yasuharu Watanabe1,
- Tomoya Nakamura1,
- Sho Ishikawa1,
- Shiho Fujisaka2,
- Isao Usui2,
- Koichi Tsuneyama3,
- Yoshinori Ichihara4,
- Tsutomu Wada4,
- Yoichiro Hirata5,
- Takayoshi Suganami6,
- Hirofumi Izaki7,
- Shizuo Akira8,
- Kensuke Miyake9,
- Hiro-omi Kanayama7,
- Michio Shimabukuro10,
- Masataka Sata5,
- Toshiyasu Sasaoka4,
- Yoshihiro Ogawa6,
- Kazuyuki Tobe2,
- Kiyoshi Takatsu1,11 and
- Yoshinori Nagai1⇓
- 1Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan
- 2Department of First Internal Medicine, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan
- 3Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan
- 4Department of Clinical Pharmacology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan
- 5Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
- 6Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
- 7Department of Urology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
- 8Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
- 9Division of Infectious Genetics, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- 10Department of Cardio-Diabetes Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
- 11Toyama Prefectural Institute for Pharmaceutical Research, Toyama, Japan
- Corresponding authors: Yoshinori Nagai, , and Kiyoshi Takatsu, .
Y.W., T.N., and Y.N. contributed equally to this work.
Recent accumulating evidence suggests that innate immunity is associated with obesity-induced chronic inflammation and metabolic disorders. Here, we show that a Toll-like receptor (TLR) protein, radioprotective 105 (RP105)/myeloid differentiation protein (MD)-1 complex, contributes to high-fat diet (HFD)-induced obesity, adipose tissue inflammation, and insulin resistance. An HFD dramatically increased RP105 mRNA and protein expression in stromal vascular fraction of epididymal white adipose tissue (eWAT) in wild-type (WT) mice. RP105 mRNA expression also was significantly increased in the visceral adipose tissue of obese human subjects relative to nonobese subjects. The RP105/MD-1 complex was expressed by most adipose tissue macrophages (ATMs). An HFD increased RP105/MD-1 expression on the M1 subset of ATMs that accumulate in eWAT. Macrophages also acquired this characteristic in coculture with 3T3-L1 adipocytes. RP105 knockout (KO) and MD-1 KO mice had less HFD-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance compared with wild-type (WT) and TLR4 KO mice. Finally, the saturated fatty acids, palmitic and stearic acids, are endogenous ligands for TLR4, but they did not activate RP105/MD-1. Thus, the RP105/MD-1 complex is a major mediator of adipose tissue inflammation independent of TLR4 signaling and may represent a novel therapeutic target for obesity-associated metabolic disorders.
Y.N. and K.Ta. are both senior authors.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1182/-/DC1.
T.N. is currently affiliated with the R&D Center, Ikeda Mohando, Toyama, Japan.
Y.H. is currently affiliated with the Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
- Received August 24, 2011.
- Accepted February 3, 2012.
- © 2012 by the American Diabetes Association.
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