Identification and molecular mechanism of anti-aging food factors which activate an anti-obese hormone

• Project/Area Number: 19H02906
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 38050:Food sciences-related
• Research Institution: The University of Tokyo
• Principal Investigator: Shimizu Makoto 東京大学, 大学院農学生命科学研究科(農学部), 特任准教授 (40409008)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2021: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2020: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2019: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: FGF21 / ATF4 / 抗老化 / 食品成分 / 老化 / アンチエイジング

Outline of Research at the Start

我が国は超高齢社会であり、高齢者の健康寿命の延伸が重要な課題である。FGF21（fibroblast growth factor 21）は肝臓で合成・分泌されるホルモン分子であり抗肥満効果や寿命延伸効果が報告されている。一方で、FGF21の強制発現マウスが長寿命であることが報告されている。また、このマウスのエネルギー代謝は良好であることから、FGF21が健康寿命を延伸する重要な分子である可能性が考えられる。本研究では、老化モデルマウスなどを用いてFGF21やその発現制御因子による抗老化シグナルの同定を目指す。また、この経路を活性化する機能性食品成分の同定を目指す。

Outline of Final Research Achievements

FGF21(fibroblast growth factor 21) is an anti-obese hormone secreted from the liver. Our previous study showed that ATF4 is an important regulator of FGF21 expression. Because overexpression of FGF21 leads to extend life span. This study investigate a role of FGF21 and ATF4 on aging. Experiments of ATF4 overexpression and functional food factors which activate ATF4 showed that several expression of several genes related to energy metabolism and aging are regulated by ATF4. A database analysis revealed an existence of the upstream factor which may regulate ATF4-FGF21 pathway.

Academic Significance and Societal Importance of the Research Achievements

我が国は超高齢社会であり、高齢者の増加に伴う医療・介護費の膨大化が深刻な問題となっている。また、高齢者自身のQOL・ADLの維持と増進のためにも健康寿命延伸が重要な課題である。FGF21は、肝臓から分泌され脂肪組織などエネルギー代謝に関わる組織に作用し様々なエネルギー代謝改善効果を有する。またFGF21は寿命延伸効果も有しており、健康寿命延伸に繋がる因子であることが予想された。FGF21の活性は遺伝子発現レベルでの制御が重要であるため、本研究ではその上流及び下流シグナルの解析を実施した。本研究成果により、健康寿命の新たな制御シグナルの同定につながることが期待される。

Research Products

• [Journal Article] Sesamin and Hepatic Metabolites Derived from Sesamin and Episesamin Antagonize Farnesoid X Receptor and Reduce the Expression of Gluconeogenesis-Related Genes (2022)
  • Author(s): SASAKI Takashi、OKUDA Mako、HONG Tzu-Wen、WATANABE Yuichi、TAKAHASHI Yu、SHIMIZU Makoto、YAMAUCHI Yoshio、SATO Ryuichiro
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 68 Issue: 1 Pages: 55-64
  • DOI: 10.3177/jnsv.68.55
  • NAID: 130008164780
  • ISSN: 0301-4800, 1881-7742
  • Year and Date: 2022-02-28
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endocrine Fibroblast Growth Factors in Relation to Stress Signaling (2022)
  • Author(s): Shimizu Makoto、Sato Ryuichiro
  • Journal Title: Cells Volume: 11 Issue: 3 Pages: 505-505
  • DOI: 10.3390/cells11030505
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Maslinic acid activates mTORC1 and human TGR5 and induces skeletal muscle hypertrophy (2021)
  • Author(s): Murata Shotaro、Sasaki Takashi、Yamauchi Yuki、Shimizu Makoto、Sato Ryuichiro
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 85 Issue: 11 Pages: 2311-2321
  • DOI: 10.1093/bbb/zbab151
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Insulin-induced genes INSIG1 and INSIG2 mediate oxysterol-dependent activation of the PERK?eIF2α?ATF4 axis (2021)
  • Author(s): Watanabe Yuichi、Sasaki Takashi、Miyoshi Shoko、Shimizu Makoto、Yamauchi Yoshio、Sato Ryuichiro
  • Journal Title: Journal of Biological Chemistry Volume: 297 Issue: 2 Pages: 100989-100989
  • DOI: 10.1016/j.jbc.2021.100989
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparison of gene expression and activation of transcription factors in organoid-derived monolayer intestinal epithelial cells and organoids (2021)
  • Author(s): Takahashi Yu、Inoue Yu、Kuze Keitaro、Sato Shintaro、Shimizu Makoto、Kiyono Hiroshi、Yamauchi Yoshio、Sato Ryuichiro
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 85 Issue: 10 Pages: 2137-2144
  • DOI: 10.1093/bbb/zbab136
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Orange peel extract reduces the inflammatory state of skeletal muscle after downhill running via an increase in IL-1RA (2021)
  • Author(s): Suzuki Toshihide、Shimizu Makoto、Yamauchi Yoshio、Sato Ryuichiro
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 85 Issue: 6 Pages: 1506-1513
  • DOI: 10.1093/bbb/zbab049
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Muscle-specific TGR5 overexpression improves glucose clearance in glucose-intolerant mice (2021)
  • Author(s): Sasaki Takashi、Watanabe Yuichi、Kuboyama Ayane、Oikawa Akira、Shimizu Makoto、Yamauchi Yoshio、Sato Ryuichiro
  • Journal Title: Journal of Biological Chemistry Volume: 296 Pages: 100131-100131
  • DOI: 10.1074/jbc.ra120.016203
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional effect of nobiletin as a food-derived allosteric modulator of mouse CRFR2β in skeletal muscle (2020)
  • Author(s): Chikazawa Miho、Moriwaki Yoshitaka、Uramoto Mari、Yamauchi Yoshio、Shimizu Makoto、Shimizu Kentaro、Sato Ryuichiro
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 529 Issue: 2 Pages: 328-334
  • DOI: 10.1016/j.bbrc.2020.03.189
  • Peer Reviewed
• [Journal Article] Polymethoxyflavones in orange peel extract prevent skeletal muscle damage induced by eccentric exercise in rats (2020)
  • Author(s): Suzuki Toshihide、Shimizu Makoto、Yamauchi Yoshio、Sato Ryuichiro
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 85 Issue: 2 Pages: 440-446
  • DOI: 10.1093/bbb/zbaa036
  • Peer Reviewed / Open Access
• [Presentation] 大豆タンパク質βコングリシニンによる代謝改善効果 (2022)
  • Author(s): 清水誠
  • Organizer: 第42回日本肥満学会・第39回日本肥満症治療学会学術集会
  • Invited
• [Presentation] 低タンパク質誘導性脂肪肝を制御する新たな転写因子の同定 (2021)
  • Author(s): 清水誠、鄭力榕 、不野歩美、梅村真理子、高橋勇二、山内祥生、佐藤隆一郎
  • Organizer: 日本アミノ酸学会第 15 回学術大会
• [Presentation] 非アルコール性脂肪肝を制御する新たな転写因子の同定 (2020)
  • Author(s): 清水誠、不野歩美、梅村真理子、高橋勇二、山内祥生、佐藤隆一郎
  • Organizer: 日本農芸化学会
• [Presentation] 核内受容体LXRによる骨格筋機能制御 (2020)
  • Author(s): 清水誠、小野敦子、近澤未歩、山内祥生、佐藤隆一郎1
  • Organizer: 日本栄養・食糧学会