title: Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis.
abstract: In obesity, a paracrine loop between adipocytes and macrophages augments chronic inflammation of adipose tissue, thereby inducing systemic insulin resistance and ectopic lipid accumulation. Obese adipose tissue contains a unique histological structure termed crown-like structure (CLS), where adipocyte-macrophage crosstalk is known to occur in close proximity. Here we show that Macrophage-inducible C-type lectin (Mincle), a pathogen sensor for Mycobacterium tuberculosis, is localized to macrophages in CLS, the number of which correlates with the extent of interstitial fibrosis. Mincle induces obesity-induced adipose tissue fibrosis, thereby leading to steatosis and insulin resistance in liver. We further show that Mincle in macrophages is crucial for CLS formation, expression of fibrosis-related genes and myofibroblast activation. This study indicates that Mincle, when activated by an endogenous ligand released from dying adipocytes, is involved in adipose tissue remodelling, thereby suggesting that sustained interactions between adipocytes and macrophages within CLS could be a therapeutic target for obesity-induced ectopic lipid accumulation.
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: 1] Department of Organ Network and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan [2] Japan Science and Technology Agency, PRESTO, Tokyo, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suganami
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Chikara
authors.initials: C
authors.lastname: Komiya
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Kozue
authors.initials: K
authors.lastname: Ochi
authors.affiliation: Department of Organ Network and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Ibuki
authors.initials: I
authors.lastname: Shirakawa
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Hamaguchi
authors.affiliation: 1] Department of Cardiovascular Medicine, The University of Tokyo, Tokyo 113-8655, Japan [2] Translational Systems Biology and Medicine Initiative, The University of Tokyo, Tokyo 113-8655, Japan [3] Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Department of Cardiovascular Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Fujisawa 251-8555, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Kimura
authors.affiliation: Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Department of Regenerative Medicine, Center for Matrix Biology and Medicine, Tokai University School of Medicine, Isehara 259-1193, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Inagaki
authors.affiliation: Department of Home Economics, Otsuma Women's University, Tokyo 102-8357, Japan.
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Aoe
authors.affiliation: Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Yamasaki
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000273:Adipose Tissue / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D002135:Calcium-Binding Proteins; D005355:Fibrosis; D007249:Inflammation / Q000378:metabolism; D007333:Insulin Resistance; D037181:Lectins, C-Type / Q000378:metabolism*; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled
chemical_list: C000634132:Adgre1 protein, mouse; D002135:Calcium-Binding Proteins; C113583:Clecsf8 protein, mouse; D037181:Lectins, C-Type; D008024:Ligands; D008055:Lipids; D008565:Membrane Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled