The radioprotective 105/MD-1 complex contributes to diet-induced obesity and adipose tissue inflammation

Yasuharu Watanabe, Tomoya Nakamura, Sho Ishikawa, Shiho Fujisaka, Isao Usui, Koichi Tsuneyama, Yoshinori Ichihara, Tsutomu Wada, Yoichiro Hirata, Takayoshi Suganami, Hirofumi Izaki, Shizuo Akira, Kensuke Miyake, Hiro Omi Kanayama, Michio Shimabukuro, Masataka Sata, Toshiyasu Sasaoka, Yoshihiro Ogawa, Kazuyuki Tobe, Kiyoshi TakatsuYoshinori Nagai

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31 Citations (Scopus)

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 obesityassociated metabolic disorders.

Original languageEnglish
Pages (from-to)1199-1209
Number of pages11
JournalDiabetes
Volume61
Issue number5
DOIs
Publication statusPublished - May 2012

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Watanabe, Y., Nakamura, T., Ishikawa, S., Fujisaka, S., Usui, I., Tsuneyama, K., Ichihara, Y., Wada, T., Hirata, Y., Suganami, T., Izaki, H., Akira, S., Miyake, K., Kanayama, H. O., Shimabukuro, M., Sata, M., Sasaoka, T., Ogawa, Y., Tobe, K., ... Nagai, Y. (2012). The radioprotective 105/MD-1 complex contributes to diet-induced obesity and adipose tissue inflammation. Diabetes, 61(5), 1199-1209. https://doi.org/10.2337/db11-1182