Molecular mechanism of M2 macrophage activation and insulin resistance associated with obesity
| Project/Area Number |
18H02860
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Kubota Naoto 東京大学, 医学部附属病院, 准教授 (50396719)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| 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)
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| Keywords | 糖尿病 / 肥満 |
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| 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.
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| 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。
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Report
(4 results)
Research Products
(41 results)
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[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.
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Journal Title
Gut
Volume: 70
Pages: 180-193
Related Report
Peer Reviewed
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[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.
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Journal Title
Mol. Cell
Volume: 79
Pages: 43-53
Related Report
Peer Reviewed
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[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
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Journal Title
Molecular Neurodegeneration
Volume: 14
Issue: 1
Pages: 15-15
DOI
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
Nature Communications
Volume: 10
Issue: 1
Pages: 1-16
DOI
Related Report
Peer Reviewed / Open Access
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[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
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Journal Title
Mol. Cell Biol.
Volume: 38
Issue: 16
Pages: 81-91
DOI
Related Report
Peer Reviewed / Open Access
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[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
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Journal Title
Mol. Cell Biol.
Volume: 38
Related Report
Peer Reviewed / Open Access
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[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
Invited
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[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
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[Book] 内科2020
Author(s)
窪田直人
Total Pages
2
Publisher
南江堂
Related Report
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[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
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[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
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