title: Visualized macrophage dynamics and significance of S100A8 in obese fat.
abstract: Chronic low-grade inflammation of adipose tissue plays a crucial role in the pathophysiology of obesity. Immunohistological microscopic analysis in obese fat tissue has demonstrated the infiltration of several immune cells such as macrophages, but dynamics of immune cells have not been fully elucidated and clarified. Here, by using intravital multiphoton imaging technique, to our knowledge for the first time, we analyzed and visualized the inflammatory processes in adipose tissue under high-fat and high-sucrose (HF/HS) diet with lysozyme M-EGFP transgenic (LysM(EGFP)) mice whose EGFP was specifically expressed in the myelomonocytic lineage. Mobility of LysM(EGFP)-positive macrophages was shown to be activated just 5 d after HF/HS diet, when the distinct hypertrophy of adipocytes and the accumulation of macrophages still have not become prominent. Significant increase of S100A8 was detected in mature adipocyte fraction just 5 d after HF/HS diet. Recombinant S100A8 protein stimulated chemotactic migration in vitro and in vivo, as well as induced proinflammatory molecules, both macrophages and adipocytes, such as TNF-α and chemokine (C-C motif) ligand 2. Finally, an antibody against S100A8 efficiently suppressed the HF/HS diet-induced initial inflammatory change, i.e., increased mobilization of adipose LysM(EGFP)-positive macrophages, and ameliorated HF/HS diet-induced insulin resistance. In conclusion, time-lapse intravital multiphoton imaging of adipose tissues identified the very early event exhibiting increased mobility of macrophages, which may be triggered by increased expression of adipose S100A8 and results in progression of chronic inflammation in situ.
authors.affiliation: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Ryohei
authors.initials: R
authors.lastname: Sekimoto
authors.affiliation: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Shiro
authors.initials: S
authors.lastname: Fukuda
authors.affiliation: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; norikazu_maeda@endmet.med.osaka-u.ac.jp mishii@icb.med.osaka-u.ac.jp.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Maeda
authors.affiliation: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Yu
authors.initials: Y
authors.lastname: Tsushima
authors.affiliation: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Keisuke
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Takuya
authors.initials: T
authors.lastname: Mori
authors.affiliation: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakatsuji
authors.affiliation: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nishizawa
authors.affiliation: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Ken
authors.initials: K
authors.lastname: Kishida
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Laboratory of Cellular Dynamics, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan; Japan Science and Technology, Core Research for Evolutionary Science and Technology, Tokyo 102-0075, Japan; and.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kikuta
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Laboratory of Cellular Dynamics, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan; Japan Science and Technology, Core Research for Evolutionary Science and Technology, Tokyo 102-0075, Japan; and.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Maijima
authors.affiliation: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Department of Metabolism and Atherosclerosis, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Funahashi
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Laboratory of Cellular Dynamics, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan; Japan Science and Technology, Core Research for Evolutionary Science and Technology, Tokyo 102-0075, Japan; and norikazu_maeda@endmet.med.osaka-u.ac.jp mishii@icb.med.osaka-u.ac.jp.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishii
authors.affiliation: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
authors.forename: Iichiro
authors.initials: I
authors.lastname: Shimomura
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis / Q000187:drug effects; D059305:Diet, High-Fat; D004822:Epididymis / Q000187:drug effects / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D007328:Insulin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D036641:Microscopy, Fluorescence, Multiphoton; D009113:Muramidase / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000906:Antibodies; D040501:Calgranulin A; D007328:Insulin; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C086145:S100a8 protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D009113:Muramidase
keywords: S100A8; adipose tissue; inflammation; macrophage; obesity
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