title: The radioprotective 105/MD-1 complex contributes to diet-induced obesity and adipose tissue inflammation.
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.
authors.affiliation: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Tomoya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Sho
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Shiho
authors.initials: S
authors.lastname: Fujisaka
authors.forename: Isao
authors.initials: I
authors.lastname: Usui
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ichihara
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Wada
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suganami
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Izaki
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Hiro-omi
authors.initials: HO
authors.lastname: Kanayama
authors.forename: Michio
authors.initials: M
authors.lastname: Shimabukuro
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sasaoka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takatsu
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nagai
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D018920:Coculture Techniques; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D004822:Epididymis; D005234:Fatty Liver / Q000209:etiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism; D007333:Insulin Resistance; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology*; D019308:Palmitic Acid; D013229:Stearic Acids; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; D004041:Dietary Fats; C490500:Ly78 protein, mouse; C113553:Ly86 protein, mouse; D008562:Membrane Glycoproteins; D013229:Stearic Acids; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019308:Palmitic Acid; C031183:stearic acid