The Radioprotective 105/MD-1 Complex Contributes to Diet-Induced Obesity and Adipose Tissue Inflammation

  1. Yoshinori Nagai1
  1. 1Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan
  2. 2Department of First Internal Medicine, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan
  3. 3Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan
  4. 4Department of Clinical Pharmacology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan
  5. 5Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
  6. 6Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
  7. 7Department of Urology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
  8. 8Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
  9. 9Division of Infectious Genetics, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
  10. 10Department of Cardio-Diabetes Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
  11. 11Toyama Prefectural Institute for Pharmaceutical Research, Toyama, Japan
  1. Corresponding authors: Yoshinori Nagai, ynagai{at}med.u-toyama.ac.jp, and Kiyoshi Takatsu, takatsuk{at}med.u-toyama.ac.jp.
  1. Y.W., T.N., and Y.N. contributed equally to this work.

Abstract

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.

Footnotes

  • Received August 24, 2011.
  • Accepted February 3, 2012.

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  1. Diabetes vol. 61 no. 5 1199-1209
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