title: Isoliquiritigenin Attenuates Adipose Tissue Inflammation in vitro and Adipose Tissue Fibrosis through Inhibition of Innate Immune Responses in Mice.
abstract: Isoliquiritigenin (ILG) is a flavonoid derived from Glycyrrhiza uralensis and potently suppresses NLRP3 inflammasome activation resulting in the improvement of diet-induced adipose tissue inflammation. However, whether ILG affects other pathways besides the inflammasome in adipose tissue inflammation is unknown. We here show that ILG suppresses adipose tissue inflammation by affecting the paracrine loop containing saturated fatty acids and TNF-α by using a co-culture composed of adipocytes and macrophages. ILG suppressed inflammatory changes induced by the co-culture through inhibition of NF-κB activation. This effect was independent of either inhibition of inflammasome activation or activation of peroxisome proliferator-activated receptor-γ. Moreover, ILG suppressed TNF-α-induced activation of adipocytes, coincident with inhibition of IκBα phosphorylation. Additionally, TNF-α-mediated inhibition of Akt phosphorylation under insulin signaling was alleviated by ILG in adipocytes. ILG suppressed palmitic acid-induced activation of macrophages, with decreasing the level of phosphorylated Jnk expression. Intriguingly, ILG improved high fat diet-induced fibrosis in adipose tissue in vivo. Finally, ILG inhibited TLR4- or Mincle-stimulated expression of fibrosis-related genes in stromal vascular fraction from obese adipose tissue and macrophages in vitro. Thus, ILG can suppress adipose tissue inflammation by both inflammasome-dependent and -independent manners and attenuate adipose tissue fibrosis by targeting innate immune sensors.
authors.affiliation: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, JAPAN.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, JAPAN.|JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, JAPAN.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, JAPAN.|Toyama Prefectural Institute for Pharmaceutical Research, 17-1 Nakataikouyama, Imizu City, Toyama 939-0363, JAPAN.
authors.forename: Hiroe
authors.initials: H
authors.lastname: Honda
authors.affiliation: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, JAPAN.
authors.forename: Naoki
authors.initials: N
authors.lastname: Okamoto
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, JAPAN.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, JAPAN.
authors.forename: Takeru
authors.initials: T
authors.lastname: Hamashima
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, JAPAN.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, JAPAN.
authors.forename: Miyako
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, JAPAN.|Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, JAPAN.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suganami
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, JAPAN.
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sasahara
authors.affiliation: Division of Infectious Genetics, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, JAPAN.|Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, JAPAN.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, JAPAN.|Toyama Prefectural Institute for Pharmaceutical Research, 17-1 Nakataikouyama, Imizu City, Toyama 939-0363, JAPAN.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takatsu
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation; D047188:Chalcones / Q000494:pharmacology* / Q000627:therapeutic use; D018920:Coculture Techniques; D059305:Diet, High-Fat; D005355:Fibrosis / Q000517:prevention & control; D007113:Immunity, Innate / Q000187:drug effects; D058847:Inflammasomes / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D019899:Paracrine Communication; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D047188:Chalcones; D058847:Inflammasomes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C040920:isoliquiritigenin