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Uncovering the mechanism of BAT differentiation via DNA methylation by ACE2/Ang1-7

Research Project

Project/Area Number 20K08165
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionOsaka City General Hospital (2022-2023)
Kyoto Prefectural University of Medicine (2020-2021)

Principal Investigator

Mori Jun  地方独立行政法人大阪市民病院機構大阪市立総合医療センター(臨床研究センター), 臨床研究センター, 部長 (20750011)

Co-Investigator(Kenkyū-buntansha) 森元 英周  京都府立医科大学, 医学(系)研究科(研究院), 助教 (20827539)
中島 久和  京都府立医科大学, 医学(系)研究科(研究院), 特任講師 (80363985)
Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsACE2 / Angiotensin 1-7 / BAT / obesity / Ang1-7 / 褐色脂肪細胞 / ベージュ化 / メチル化 / 肥満 / 小児肥満 / 褐色脂肪
Outline of Research at the Start

褐色脂肪細胞の人為的調節は、脂肪組織量のコントロールを可能とし、引いては肥満症の撲滅を可能とする。研究代表者は2014年より褐色脂肪細胞分化増殖の分子機構としてアンジオテンシン変換酵素2 (ACE2)/アンジオテンシン1-7 (Ang1-7)システムに着目し、いくつかの分子機構を解明している。今回ACE2/Ang1-7システムの転写制御による新機構の端緒となるデータを得たため、転写複合体PRDM16/EHMT1のメチル化による制御機構の解明を目的とした研究を提案する。研究成果は上述のように抗肥満症薬剤の開発に繋がると期待される。

Outline of Final Research Achievements

We induced obesity in young mice by feeding them a high-fat diet for one month, followed by a one-month treatment with Ang1-7 and recombinant human ACE2 (rhACE2). Both groups exhibited weight loss accompanied by increased oxygen consumption, improved glucose tolerance, and a reduction in white adipose tissue. Additionally, there was an increase in the weight of brown adipose tissue (BAT), with enhanced expression of differentiation and proliferation markers. When comparing the effects of Ang1-7 in obese young and adult mice, the adult mice showed a decrease in BAT weight, whereas young mice exhibited an increase in BAT weight and a reduction in the number of large lipid droplets. These findings suggest that anti-obesity treatments targeting BAT may be more effective in children than in adults.

Academic Significance and Societal Importance of the Research Achievements

本研究ではrhACE2とAng1-7ともに抗肥満効果があることを確認したが、rhACE2はWATをベージュ化することでより強い抗肥満効果を示した。rhACE2のベージュ化には、EHMT1を介したH3K9のジメチル化、GCN5/PCAFによるH3K9のアセチル化とHDAC3の発現低下によるH3K27のアセチル化が関与している可能性を示した。またrhACE/Ang1-7による抗肥満効果は若年マウスほど効果があり、BAT重量に変化や脂肪組成にも違いが生じることを確認した。この月齢によるBATへの反応の違いは、将来的なBATをターゲットにした抗肥満薬の創薬開発に役立つと考えられる。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (12 results)

All 2023 2022 2021 Other

All Int'l Joint Research (2 results) Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 6 results) Presentation (3 results) Remarks (1 results)

  • [Int'l Joint Research] University of Alberta(カナダ)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] アルバータ大学(カナダ)

    • Related Report
      2020 Research-status Report
  • [Journal Article] Association of Type 2 Deiodinase Thr92Ala Polymorphism with Pediatric Obesity in Japanese Children: A Case-Control Study2022

    • Author(s)
      Ota Takeshi、Mori Jun、Kawabe Yasuhiro、Morimoto Hidechika、Fukuhara Shota、Kodo Kazuki、Sugimoto Satoru、Kosaka Kitaro、Nakajima Hisakazu、Hosoi Hajime
    • Journal Title

      Children

      Volume: 9 Issue: 10 Pages: 1421-1421

    • DOI

      10.3390/children9101421

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inulin reduces visceral adipose tissue mass and improves glucose tolerance through altering gut metabolites2022

    • Author(s)
      Nakajima Hanako、Nakanishi Naoko、Miyoshi Tomoki、Okamura Takuro、Hashimoto Yoshitaka、Senmaru Takafumi、Majima Saori、Ushigome Emi、Asano Mai、Yamaguchi Mihoko、Mori Jun、Sakui Norihiro、Sasano Ryoichi、Yamazaki Masahiro、Hamaguchi Masahide、Fukui Michiaki
    • Journal Title

      Nutrition & Metabolism

      Volume: 19 Issue: 1 Pages: 19-19

    • DOI

      10.1186/s12986-022-00685-1

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Thyroid hypogenesis is associated with a novel AKT3 germline variant that causes megalencephaly and cortical malformation2022

    • Author(s)
      Mori Jun、Hasegawa Tatsuji、Miyamoto Yosuke、Kitamura Kazumasa、Morimoto Hidechika、Tozawa Takenori、Pooh Ritsuko Kimata、Chiyonobu Tomohiro
    • Journal Title

      Human Genome Variation

      Volume: 9 Issue: 1 Pages: 18-18

    • DOI

      10.1038/s41439-022-00197-7

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Partially Hydrolyzed Guar Gum Suppresses the Development of Sarcopenic Obesity2022

    • Author(s)
      Okamura T, Hamaguchi M, Mori J, Yamaguchi M, Mizushima K, Abe A, Ozeki M, Sasano R, Naito Y, Fukui M
    • Journal Title

      Nutrients

      Volume: 14 Issue: 6 Pages: 1157-1157

    • DOI

      10.3390/nu14061157

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of lipid metabolism exerts antitumor effects on rhabdomyosarcoma2021

    • Author(s)
      Miyagaki S, Kikuchi K, Mori J, Lopaschuk GD, Iehara T, Hosoi H
    • Journal Title

      Cancer Med

      Volume: 10 Issue: 18 Pages: 6442-6455

    • DOI

      10.1002/cam4.4185

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ILC2s Improve Glucose Metabolism Through the Control of Saturated Fatty Acid Absorption Within Visceral Fat2021

    • Author(s)
      Okamura T, Hashimoto Y, Mori J, Yamaguchi M, Majima S, Senmaru T, Ushigome E, Nakanishi N, Asano M, Yamazaki M, Takakuwa H, Satoh T, Akira S, Hamaguchi M, Fukui M
    • Journal Title

      Front Immunol

      Volume: 12 Pages: 669629-669629

    • DOI

      10.3389/fimmu.2021.669629

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Persistence to growth hormone treatment and clinical characteristics of paediatric patients with growth hormone deficiency: a retrospective study.2023

    • Author(s)
      Mori J, Sato Y, Dateki S
    • Organizer
      The 61st Annual ESPE Meeting 2023
    • Related Report
      2023 Annual Research Report
  • [Presentation] GH replacement therapy with once-weekly somapacitan in children with GH deficiency is effective and well-tolerated: 2-year results from REAL4.2023

    • Author(s)
      Miller B, Blair J, Rasmussen MH, Maniatis A, Mori J, Bottcher V, Bang R, Polak M, Horikawa R
    • Organizer
      The 61st Annual ESPE Meeting 2023
    • Related Report
      2023 Annual Research Report
  • [Presentation] Predicting Average IGF-I concentration for once-weekly Somapacitan in children with growth hormone deficiency.2023

    • Author(s)
      Backeljauw P, Lyauk YK, Blair JC, Miller BS, Mori J, Rasmussen MH, Kildemoes RJ
    • Organizer
      The 61st Annual ESPE Meeting 2023
    • Related Report
      2023 Annual Research Report
  • [Remarks] The Oudit Research Program

    • URL

      https://www.ualberta.ca/department-of-medicine/oudit/index.html

    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2025-01-30  

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