title: ER Stress Protein CHOP Mediates Insulin Resistance by Modulating Adipose Tissue Macrophage Polarity.
abstract: Obesity represents chronic inflammatory states promoted by pro-inflammatory M1-macrophage infiltration into white adipose tissue (WAT), thereby inducing insulin resistance. Herein, we demonstrate the importance of an ER stress protein, CHOP, in determining adipose tissue macrophage (ATM) polarity and systemic insulin sensitivity. A high-fat diet (HFD) enhances ER stress with CHOP upregulation in adipocytes. CHOP deficiency prevents HFD-induced insulin resistance and glucose intolerance with ATM M2 predomination and Th2 cytokine upregulation in WAT. Whereas ER stress suppresses Th2 cytokine expression in cultured adipocytes, CHOP knockdown inhibits this downregulation. In contrast, macrophage responsiveness to Th1/Th2 cytokines is unchanged regardless of whether CHOP is expressed. Furthermore, bone marrow transplantation experiments showed recipient CHOP to be the major determinant of ATM polarity. Thus, CHOP in adipocytes plays important roles in ATM M1 polarization by altering WAT micro-environmental conditions, including Th2 cytokine downregulation. This molecular mechanism may link adipose ER stress with systemic insulin resistance.
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Tohoku University International Advanced Research and Education Organization, Frontier Research Institute for Interdisciplinary Science, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
authors.forename: Junhong
authors.initials: J
authors.lastname: Gao
authors.affiliation: Division of Diabetes and Metabolism, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ishigaki
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Shojiro
authors.initials: S
authors.lastname: Sawada
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Uno
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Kaneko
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Sohei
authors.initials: S
authors.lastname: Tsukita
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Asao
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Junta
authors.initials: J
authors.lastname: Imai
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Division of Molecular Biology, Institute for Genome Research, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Oyadomari
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Agency for Medical Research and Development-Core Research for Evolutional Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo 100-1004, Japan. Electronic address: katagiri@med.tohoku.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000502:physiology; D052436:Adipose Tissue, White / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D015536:Down-Regulation / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D018149:Glucose Intolerance / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D007333:Insulin Resistance / Q000502:physiology*; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D018417:Th1 Cells / Q000378:metabolism / Q000502:physiology; D018418:Th2 Cells / Q000378:metabolism / Q000502:physiology; D051742:Transcription Factor CHOP / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D016207:Cytokines; C497250:Ddit3 protein, mouse; D051742:Transcription Factor CHOP
keywords: ER stress; M2 macrophage; adipose tissue macrophage; insulin resistance; macrophage polarization