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Molecular mechanism of M2 macrophage activation and insulin resistance associated with obesity

Research Project

Project/Area Number 18H02860
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 54040:Metabolism and endocrinology-related
Research InstitutionThe University of Tokyo

Principal Investigator

Kubota Naoto  東京大学, 医学部附属病院, 准教授 (50396719)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords糖尿病 / 肥満
Outline of Final Research Achievements

We demonstrate that, the IL-4/Irs2/Akt pathway is selectively impaired, along with decreased macrophage Irs2 expression, although IL-4/STAT6 pathway is maintained. Indeed, myeloid cell-specific Irs2-deficient mice show impairment of IL-4-induced M2a-subtype macrophage activation, as a result of stabilization of the FoxO1/HDAC3/NCoR1 corepressor complex, resulting in insulin resistance under the HF diet condition. Moreover, the reduction of macrophage Irs2 expression is mediated by hyperinsulinemia via the insulin receptor (IR). In myeloid cell-specific IR-deficient mice, the IL-4/Irs2 pathway is preserved in the macrophages, which results in a reduced degree of insulin resistance, because of the lack of IR-mediated downregulation of Irs2. We conclude that downregulation of Irs2 in macrophages caused by hyperinsulinemia is responsible for systemic insulin resistance via impairment of M2a-subtype macrophage activation in obesity.

Academic Significance and Societal Importance of the Research Achievements

生理的状態においては、M2a-subtypeマクロファージは脂肪細胞の恒常性維持に重要な役割を果たしていると考えられるが、高インスリン血症が持続すると、病的な脂肪細胞肥大化の亢進は脂肪細胞のインスリン感受性を落としM1マクロファージの浸潤や活性化を惹起し、M2a-subtypeマクロファージの活性化も低下するため、インスリン抵抗性を呈するようになると考えられる。高インスリン血症をきたさない治療が重要であることが示唆された。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (41 results)

All 2021 2020 2019 2018

All Journal Article (13 results) (of which Peer Reviewed: 13 results,  Open Access: 7 results) Presentation (15 results) (of which Int'l Joint Research: 2 results,  Invited: 7 results) Book (13 results)

  • [Journal Article] LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover.2021

    • Author(s)
      Tanaka Y, Shimanaka Y, Caddeo A, Kubo T, Mao Y, Kubota T, Kubota N, Yamauchi T, Mancina RM, Baselli G, Luukkonen P, Pihlajamaki J, Yki-Jarvinen H, Valenti L, Arai H, Romeo S, Kono N.
    • Journal Title

      Gut

      Volume: 70 Pages: 180-193

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sex-related differences in the effects of nutritional status and body composition on functional disability in the elderly2021

    • Author(s)
      Sawada Mika、Kubota Naoto、Sekine Rie、Yakabe Mitsutaka、Kojima Taro、Umeda-Kameyama Yumi、Usami Satoshi、Akishita Masahiro、Ogawa Sumito
    • Journal Title

      PLOS ONE

      Volume: 16 Issue: 2 Pages: 0246276-0246276

    • DOI

      10.1371/journal.pone.0246276

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Diets with high carbohydrate contents were associated with refeeding hypophosphatemia: A retrospective study in Japanese inpatients with anorexia nervosa.2021

    • Author(s)
      Yamazaki T, Inada S, Sawada M, Sekine R, Kubota N, Fukatsu K, Yoshiuchi K.
    • Journal Title

      Int J Eat Disord.

      Volume: 54 Issue: 1 Pages: 88-94

    • DOI

      10.1002/eat.23416

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Association between tear and blood glucose concentrations: Random intercept model adjusted with confounders in tear samples negative for occult blood2020

    • Author(s)
      Aihara Masakazu、Kubota Naoto、Minami Takahiro、Shirakawa Rika、Sakurai Yoshitaka、Hayashi Takanori、Iwamoto Masahiko、Takamoto Iseki、Kubota Tetsuya、Suzuki Ryo、Usami Satoshi、Jinnouchi Hideaki、Aihara Makoto、Yamauchi Toshimasa、Sakata Toshiya、Kadowaki Takashi
    • Journal Title

      Journal of Diabetes Investigation

      Volume: 12 Issue: 2 Pages: 266-276

    • DOI

      10.1111/jdi.13344

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Insulin- and Lipopolysaccharide-Mediated Signaling in Adipose Tissue Macrophages Regulates Postprandial Glycemia through Akt-mTOR Activation.2020

    • Author(s)
      Toda G, Soeda K, Okazaki Y, Kobayashi N, Masuda Y, Arakawa N, Suwanai H, Masamoto Y, Izumida Y, Kamei N, Sasako T, Suzuki R, Kubota T, Kubota N, Kurokawa M, Tobe K, Noda T, Honda K, Accili D, Yamauchi T, Kadowaki T, Ueki K.
    • Journal Title

      Mol. Cell

      Volume: 79 Pages: 43-53

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effect of home enteral nutrition after pancreaticoduodenectomy.2019

    • Author(s)
      Ito D, Arita J, Yamamoto M, Akamatsu N, Kaneko J, Ijichi H, Kubota N, Sakamoto Y, Kokudo N, Hasegawa K
    • Journal Title

      Nutrition

      Volume: 60 Pages: 206-211

    • DOI

      10.1016/j.nut.2018.10.007

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] NAPE-PLD controls OEA synthesis and fat absorption by regulating lipoprotein synthesis in an in vitro model of intestinal epithelial cells2019

    • Author(s)
      Miki Igarashi、Kazuhide Watanabe、Tsuyoshi Tsuduki、Ikuo Kimura、Naoto Kubota
    • Journal Title

      The FASEB Journal

      Volume: 33 Issue: 3 Pages: 3167-3179

    • DOI

      10.1096/fj.201801408r

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer’s disease2019

    • Author(s)
      Tomoko Wakabayashi, Kazuki Yamaguchi, Kentaro Matsui, Toshiharu Sano, Tetsuya Kubota, Tadafumi Hashimoto, Ayako Mano, Kaoru Yamada, Yuko Matsuo, Naoto Kubota, Takashi Kadowaki, Takeshi Iwatsubo
    • Journal Title

      Molecular Neurodegeneration

      Volume: 14 Issue: 1 Pages: 15-15

    • DOI

      10.1186/s13024-019-0315-7

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism2019

    • Author(s)
      Sasako T., Ohsugi M., Kubota N., Itoh S., Okazaki Y, Terai A., Kubota T., Yamashita S., Nakatsukasa K., Kamura T., Iwayama K., Tokuyama K., Kiyonari H., Furuta Y., Shibahara J., Fukayama M., Enooku K., Okushin K., Tsutsumi T., Tateishi R., Tobe K., Asahara H., Koike K., *Kadowaki T. & *Ueki K.
    • Journal Title

      Nature Communications

      Volume: 10 Issue: 1 Pages: 1-16

    • DOI

      10.1038/s41467-019-08591-6

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The RNA Methyltransferase Complex of WTAP, METTL3, and METTL14 Regulates Mitotic Clonal Expansion in Adipogenesis.2018

    • Author(s)
      Kobayashi M, Ohsugi M, Sasako T, Awazawa M, Umehara T, Iwane A, Kobayashi N, Okazaki Y, Kubota N, Suzuki R, Waki H, Horiuchi K, Hamakubo T, Kodama T, Aoe S, Tobe K, Kadowaki T, Ueki K
    • Journal Title

      Mol. Cell Biol.

      Volume: 38 Issue: 16 Pages: 81-91

    • DOI

      10.1128/mcb.00116-18

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The RNA Methyltransferase Complex of WTAP, METTL3, and METTL14 Regulates Mitotic Clonal Expansion in Adipogenesis.2018

    • Author(s)
      Kobayashi M, Ohsugi M, Sasako T, Awazawa M, Umehara T, Iwane A, Kobayashi N, Okazaki Y, Kubota N, Suzuki R, Waki H, Horiuchi K, Hamakubo T, Kodama T, Aoe S, Tobe K, Kadowaki T, Ueki K
    • Journal Title

      Mol. Cell Biol.

      Volume: 38

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Gα12/13-coupled receptor LPA4 limits proper adipose tissue expansion and remodeling in diet-induced obesity2018

    • Author(s)
      Yanagida Keisuke、Igarashi Hidemitsu、Yasuda Daisuke、Kobayashi Daiki、Ohto-Nakanishi Takayo、 Akahoshi Noriyuki、Sekiba Atsushi、Toyoda Tsudoi、Ishijima Tomoko、Nakai Yuji、Shojima Nobuhiro、Kubota Naoto、Abe Keiko、Kadowaki Takashi、Ishii Satoshi、Shimizu Takao
    • Journal Title

      JCI Insight

      Volume: 3 Pages: 97293-97293

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity2018

    • Author(s)
      Kubota Tetsuya、Inoue Mariko、Kubota Naoto、Takamoto Iseki、Mineyama Tomoka、Iwayama Kaito、 Tokuyama Kumpei、Moroi Masao、Ueki Kohjiro、Yamauchi Toshimasa、Kadowaki Takashi
    • Journal Title

      Nature Communications

      Volume: 9 Pages: 4863-4863

    • NAID

      120007133395

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Development of the Noninvasive Diabetes Monitoring Method2020

    • Author(s)
      Masakazu Aihara, Naoto Kubota, Takashi Kadowaki
    • Organizer
      American Diabetes Association, 81st Scientific Sessions
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Development of the Noninvasive Diabetes Monitoring Method2020

    • Author(s)
      Masakazu Aihara, Naoto Kubota, Takashi Kadowaki
    • Organizer
      European Association for the Study of Diabetes, 56th Annual Meeting 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 糖尿病診療に必要な知識 経腸栄養・静脈栄養2020

    • Author(s)
      窪田直人
    • Organizer
      第54回糖尿病学の進歩
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 糖尿病患者の食事療法2020

    • Author(s)
      窪田直人
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 「TP03 SGLT2 i はなぜ心不全を予防し治療できるのか?The Benefits and Its Mechanisms of SGLT2 Inhibitors in Heart Failure」2020

    • Author(s)
      窪田直人, 相原允一, 和田亘弘, 林高則, 窪田哲也
    • Organizer
      第85回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] シンポジウム「糖尿病とNASH/NAFLD:分子メカニズムと最新の治療」「肥満に伴う選択的インスリン抵抗性の分子機構―肝臓のmetabolic zonation―」2019

    • Author(s)
      窪田直人
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] パネルディスカッション:メタボリックシンドロームとしての脂肪肝「メタボリックシンドロームにおける肝臓の選択的インスリン抵抗性」2019

    • Author(s)
      窪田 直人, 窪田 哲也, 門脇 孝
    • Organizer
      第105回日本消化器病学会総会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 入院糖尿病患者における食事摂取状況と食生活背景との関連2019

    • Author(s)
      澤田実佳、長谷川陽子、金子徹治、飯室聡、関根里恵、山内敏正、窪田直人
    • Organizer
      第20回日本内分泌学会関東甲信越支部学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 血管内皮細胞のIrs2は動脈硬化に抑制的に働く2019

    • Author(s)
      窪田哲也、窪田直人、林 高則、相原允一、山内敏正、門脇 孝
    • Organizer
      第23回日本心血管内分泌学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] シンポジウム「肥満症治療における栄養~管理栄養士と医師との連携~」「内科的治療で体重をコントロールできない肥満症例への外科治療と栄養について」2019

    • Author(s)
      関根 里恵, 澤田 実佳, 若松 高太郎, 庄嶋 伸浩, 山崎 允宏, 高見 真, 中村 衣里, 吉内 一浩, 瀬戸 泰之, 山内 敏正, 窪田 直人
    • Organizer
      第40回日本肥満学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 入院糖尿病患者における食事摂取状況の検討2019

    • Author(s)
      澤田 実佳, 長谷川 陽子、高見 真, 関根 里恵, 山内 敏正, 窪田 直人
    • Organizer
      第33回日本糖尿病学会関東甲信越地方会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 骨格筋におけるインスリン受容体基質の役割の解明2019

    • Author(s)
      相原允一,窪田直人,窪田哲也,林高則,桜井賛孝,岩本真彦,山内敏正,門脇孝
    • Organizer
      第33回日本糖尿病・肥満動物学会年次学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 2型糖尿病患者における体組成の特徴に関する検討2018

    • Author(s)
      窪田 直人、澤田 実佳、高見 真、中村 衣里、前 明日美、鈴木 亮、伊地知 秀明、関根 里恵、山内 敏正、門脇 孝
    • Organizer
      第61回日本糖尿病学会年次学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 肝移植後の骨格筋量の増加に対して周術期の栄養摂取が及ぼす影響2018

    • Author(s)
      長谷川陽子、長田梨比人、伊地知秀明、関根里恵、赤松延久、野尻佳代、裵成寛、田村純人、有田淳一、冨樫順一、金子順一、長谷川潔、窪田直人
    • Organizer
      第36回日本肝移植研究会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 「肥満合併症としての肝疾患-NASHと肝細胞癌をどう捉えるか- 肥満に伴う選択的インスリン抵抗性の分子機構 肝臓のmetabolic zonation」2018

    • Author(s)
      窪田 直人, 窪田 哲也, 山内 敏正, 門脇 孝
    • Organizer
      第39回日本肥満学会総会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Book] 医学のあゆみ2021

    • Author(s)
      窪田直人, 窪田哲也, 門脇孝
    • Total Pages
      7
    • Publisher
      医師薬出版
    • Related Report
      2020 Annual Research Report
  • [Book] 内科2020

    • Author(s)
      窪田直人
    • Total Pages
      2
    • Publisher
      南江堂
    • Related Report
      2020 Annual Research Report
  • [Book] 月刊糖尿病ライフさかえ2020

    • Author(s)
      窪田直人
    • Total Pages
      2
    • Publisher
      日本糖尿病協会
    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
  • [Book] 医学と薬学2020

    • Author(s)
      窪田直人
    • Total Pages
      6
    • Publisher
      自然科学社
    • Related Report
      2020 Annual Research Report
  • [Book] 糖尿病専門医研修ガイドブック改定第八版2020

    • Author(s)
      窪田直人
    • Total Pages
      4
    • Publisher
      日本糖尿病学会
    • Related Report
      2020 Annual Research Report
  • [Book] 診断と治療2019

    • Author(s)
      窪田直人
    • Total Pages
      7
    • Publisher
      診断と治療社
    • Related Report
      2019 Annual Research Report
  • [Book] 月刊糖尿病2019

    • Author(s)
      窪田直人
    • Total Pages
      6
    • Publisher
      医学出版
    • Related Report
      2019 Annual Research Report
  • [Book] Medical Science Digest2019

    • Author(s)
      窪田直人
    • Total Pages
      4
    • Publisher
      ニュー・サイエンス社
    • Related Report
      2019 Annual Research Report
  • [Book] 糖尿病プラクティス2019

    • Author(s)
      林 高則, 窪田 直人
    • Total Pages
      3
    • Publisher
      医歯薬出版
    • Related Report
      2019 Annual Research Report
  • [Book] 内分泌・糖尿病・代謝内科2018

    • Author(s)
      窪田 直人、佐々木 元大、笹子 敬洋、門脇 孝
    • Total Pages
      5
    • Publisher
      (有)科学評論社
    • Related Report
      2018 Annual Research Report
  • [Book] 医と食2018

    • Author(s)
      窪田 哲也、窪田 直人、門脇 孝
    • Total Pages
      4
    • Publisher
      (公社)生命科学振興会「医と食」編集部
    • Related Report
      2018 Annual Research Report
  • [Book] 腎と透析2018

    • Author(s)
      窪田 直人、門脇 孝
    • Total Pages
      5
    • Publisher
      (株)東京医学社
    • Related Report
      2018 Annual Research Report
  • [Book] 内分泌・糖尿病・代謝内科2018

    • Author(s)
      桜井 賛孝、窪田 直人、門脇 孝
    • Total Pages
      5
    • Publisher
      (有)科学評論社
    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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