Development of a new anti-obesity therapy targeting hypothalamic AAA ATPase, VCP

• Project/Area Number: 17K09844
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Jichi Medical University
• Principal Investigator: Ebihara Ken 自治医科大学, 医学部, 准教授 (70362514)
• Co-Investigator(Kenkyū-buntansha): 海老原 千尋 自治医科大学, 医学部, 客員研究員 (90790915)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肥満 / レプチン / レプチン抵抗性 / 小胞体ストレス / ATP / ケトン体 / 視床下部 / 内科

Outline of Final Research Achievements

Endoplasmic reticulum (ER) stress in the hypothalamus plays a key role in the pathogenesis of leptin resistance. Since ATP treatment protects cells against ER stress, we investigated the therapeutic effects of oral 1,3-butanediol (BD) administration, which increases plasma -hydroxybutyrate and hypothalamic ATP concentrations, in diet induced obese (DIO) mice with leptin resistance. BD treatment effectively decreased food intake and body weight in DIO mice. In contrast, BD treatment had no effect in leptin deficient ob/ob mice. We also demonstrated that BD treatment decreases expressions of ER stress markers and increases phosphorylation of STAT3, a molecule of leptin signaling, in the hypothalamus. This is the first report to confirm the leptin sensitizing effect of BD treatment in leptin resistant DIO mice. The present study provides collateral evidence that the effect of BD treatment is mediated by the elevation of hypothalamic ATP concentration.

Academic Significance and Societal Importance of the Research Achievements

VCPのATPase活性阻害薬は小胞体（ER）ストレス時のATP 不足を抑制し、ERストレスの軽減とレプチン感受性などの細胞機能維持に寄与するものと考えられる。この仮説を立証し、臨床応用に結びつけるために、1,3-ブタンジオール（BD）を用いて血中ケトン体および視床下部ATP濃度を上昇させた時の体重や摂食量、視床下部におけるERストレスやレプチン感受性をマウスで検討した。これまでに、視床下部におけるERストレスとレプチン抵抗性に対するケトン体の効果に関する報告はない。本研究によりケトン体あるいは視床下部ATPを標的とした新しい肥満治療法の開発と臨床応用が実現する可能性は高い。

Research Products

• [Journal Article] The hepatokine FGF21 is crucial for peroxisome proliferator-activated receptor-α agonist-induced amelioration of metabolic disorders in obese mice. (2017)
  • Author(s): Goto T, Hirata M, Aoki Y, Iwase M, Takahashi H, Kim M, Li Y, Jheng HF, Nomura W, Takahashi N, Kim CS, Yu R, Seno S, Matsuda H, Aizawa-Abe M, Ebihara K, Itoh N, Kawada T
  • Journal Title: J Biol Chem Volume: 292 Pages: 9175-9190
  • Peer Reviewed
• [Presentation] 視床下部ATPを標的としたレプチン抵抗性改善薬の開発 (2019)
  • Author(s): 礒田雅代、海老原健、海老原千尋、村上明子、武井暁一、武井祥子、高橋学、永島秀一、石橋俊
  • Organizer: 日本内分泌学会
• [Presentation] Hypothalamic ATP has a crucial role in the pathogenesis of leptin resistance: a potential mechanism for the amelioration of leptin resistance by celastrol and withaferin A (2019)
  • Author(s): Chihiro Ebihara, Ken Ebihara, Masayo Isoda, Akiko Murakami, Daisuke Yamamuro, Manabu Takahashi, Shuichi Nagashima, Shun Ishibashi
  • Organizer: 北米内分泌学会
  • Int'l Joint Research
• [Presentation] Hypothalamic ATP up-regulation is the mechanism for the amelioration of leptin resistance by celastrol and withaferin A (2017)
  • Author(s): Chihiro Ebihara, Ken Ebihara, Masayo Isoda, Akiko Murakami, Daisuke Yamamuro, Manabu Takahashi, Shuichi Nagashima, Shun Ishibashi
  • Organizer: 53rd Annual Meeting of the European Association for the Study of Diabetes
  • Int'l Joint Research