Elucidation of the role of Pin1 in thermogenesis and temperature-dependent Pin1 degradation

• Project/Area Number: 18K19431
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: Hiroshima University
• Principal Investigator: Asano Tomoichiro 広島大学, 医系科学研究科(医), 教授 (70242063)
• Co-Investigator(Kenkyū-buntansha): 中津 祐介 広島大学, 医系科学研究科(医), 講師 (20452584)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: Pin1 / 脂肪細胞 / 熱産生 / 肥満 / 代謝 / 温度 / PRDM16 / Ｐｉｎ１ / タンパク分解 / 温熱療法

Outline of Final Research Achievements

Non-shivering thermogenesis in adipocytes provides defense against low temperatures and obesity development, but the underlying regulatory mechanism remains to be fully clarified. Adipose-specific Pin1 KO (adPin1 KO) mice showed enhanced transcription of thermogenic genes, including UCP-1, and tolerance to hypothermia when exposed to cold (temperature at 4℃). In addition, adPin1 KO mice were resistant to high fat diet-induced obesity and glucose intolerance. Searching for Pin1 binding proteins as well as subsequent overexpression and gene silencing experiments revealed that Pin1 binds to PRDM16 and thereby promotes its degradation through the ubiquitin-proteasome system.
Taken together, these observations indicate Pin1 to be a negative regulator of non-shivering thermogenesis, which involves the regulation of thermogenesis in response to nutrient conditions and cold exposure.

Academic Significance and Societal Importance of the Research Achievements

体内からの熱産生は、基礎代謝量に影響している。従って、脂肪細胞からの熱産生量の減少が、肥満や脂肪感を含めたメタボリックシンドロームの発症に影響しているが、このプロセスにPin1の発現量増加が関与していることが明らかとなった。実際、Pin1の遺伝子欠損マウスは、基礎代謝が高く、肥満に抵抗性を示す。我々は、従って、Pin1の活性を抑制する薬剤を開発し、肥満やNASHへの治療薬への応用を目指しており、社会的意義も高い。

Research Products

• [Journal Article] Prolyl isomerase Pin1 in metabolic reprogramming of cancer cells. (2020)
  • Author(s): Nakatsu, Y., Yamamotoya, T., Ueda, K., Ono, H., Inoue, MK., Matsunaga, Y., Kushiyama, A., Sakoda, H., Fujishiro, M., Matsubara, A., and Asano, T.
  • Journal Title: Cancer Lett. Volume: 470 Pages: 106-114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-inflammatory effects of miRNA-146a induced in adipose and periodontal tissues. (2020)
  • Author(s): Sanada, T., Sano, T., Sotomaru, Y., Alshargabi, R., Yamawaki, Y., Yamashita, A., Matsunaga, H., Iwashita, M., Shinjo, T., Kanematsu, T., Asano, T., and Nishimura, F.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 22 Pages: 100757-100757
  • Peer Reviewed / Open Access
• [Journal Article] Possible Involvement of Normalized Pin1 Expression Level and AMPK Activation in the Molecular Mechanisms Underlying Renal Protective Effects of SGLT2 Inhibitors in Mice. (2020)
  • Author(s): Inoue, MK., Matsunaga, Y., Nakatsu, Y., Yamamotoya, T., Ueda, K., Kushiyama, A., Sakoda, H., Fujishiro, M., Ono, H., Iwashita, M., Sano, T., Nishimura, F., Morii, K., Sasaki, K., Masaki, T., and Asano, T
  • Journal Title: Diabetol. Metab. Syndr. Volume: 11 Pages: 57-57
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16. (2019)
  • Author(s): Nakatsu, Y., Matsunaga, Y., Yamamotoya, T., Ueda, K., Ohno, H., Yoneda, M., Takahashi, K., Ishihara, H., Katagiri, H., Nishimura, F., Kanematsu, T., Yamada, T.,and Asano, T.
  • Journal Title: Cell Rep. Volume: 26 Pages: 3221-3230
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pin1 Plays Essential Roles in NASH Development by Modulating Multiple Target Proteins (2019)
  • Author(s): Inoue, MK., Nakatsu, Y., Yamamotoya, T., Hasei, S., Kanamoto, M., Naitou, M., Matsunaga, Y., Sakoda, H., Fujishiro, M., Ono, H., Kushiyama, A., and Asano, T.
  • Journal Title: Cells Volume: 8 Pages: 1545-1545
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects Against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice. (2019)
  • Author(s): Mizuno, Y., Yamamotoya, T., Nakatsu, Y., Ueda, K., Matsunaga, Y., Inoue, MK., Sakoda, H., Fujishiro, M., Ono, H., Kikuchi, T., Takahashi, M., Morii, K., Sasaki, K., Masaki, T., Asano, T., and Kushiyama, A.
  • Journal Title: Int. J. Mol. Sci. Volume: 20 Pages: 4680-4680
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl Isomerase Pin1 Binds to and Stabilizes Acetyl CoA Carboxylase 1 Protein, Thereby Supporting Cancer Cell Proliferation (2019)
  • Author(s): Ueda, K., Nakatsu, Y., Yamamotoya, T., Ono, H., Inoue, Y., Inoue, MK., Mizuno, Y., Matsunaga, Y., Kushiyama, A., Sakoda, H., Fujishiro, M., Takahashi, SI., Matsubara, A., and Asano, T.
  • Journal Title: Oncotarget Volume: 10 Pages: 1637-1648
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl isomerase Pin1 binds to and stabilizes acetyl CoA carboxylase 1 protein, thereby supporting cancer cell proliferation. (2019)
  • Author(s): Ueda K, Nakatsu Y, Yamamotoya T, Ono H, Inoue Y, Inoue MK, Mizuno Y, Matsunaga Y, Kushiyama A, Sakoda H, Fujishiro M, Takahashi SI, Matsubara A, Asano T.
  • Journal Title: Oncotarget Volume: 10 Pages: 1637-1648
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16. (2019)
  • Author(s): Nakatsu Y, Matsunaga Y, Yamamotoya T, Ueda K, Inoue MK, Mizuno Y, Nakanishi M, Sano T, Yamawaki Y, Kushiyama A, Sakoda H, Fujishiro M, Ryo A, Ono H, Minamino T, Takahashi SI, Ohno H, Yoneda M, Takahashi K, Ishihara H, Katagiri H, Nishimura F, Kanematsu T, Yamada T, Asano T.
  • Journal Title: Cell Rep Volume: 26 Pages: 3221-3230
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Xanthine Oxidase Inhibitor Febuxostat Suppresses the Progression of IgA Nephropathy, Possibly via Its Anti-Inflammatory and Anti-Fibrotic Effects in the gddY Mouse Model. (2018)
  • Author(s): Inoue MK, Yamamotoya T, Nakatsu Y, Ueda K, Inoue Y, Matsunaga Y, Sakoda H, Fujishiro M, Ono H, Morii K, Sasaki K, Masaki T, Suzuki Y, Asano T, Kushiyama A.
  • Journal Title: Int J Mol Sci. Volume: 19
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of Pin1 inhibitors and their potential as therapeutic agents. (2018)
  • Author(s): Nakatsu Y, Matsunaga Y, Ueda K, Yamamotoya T, Inoue Y, Inoue MK, Mizuno Y, Kushiyama A, Ono H, Fujishiro M, Ito H, Okabe T, Asano T.
  • Journal Title: Curr Med Chem. Volume: 10 Pages: 2174-2174
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IRS-2 deubiquitination by USP9X maintains anchorage-independent cell growth via Erk1/2 activation in prostate carcinoma cell line. (2018)
  • Author(s): Furuta H, Yoshihara H, Fukushima T, Yoneyama Y, Ito A, Worrall C, Girnita A, Girnita L, Yoshida M, Asano T, Komada M, Kataoka N, Chida K, Hakuno F, Takahashi SI.
  • Journal Title: Oncotarget Volume: 9 Pages: 33871-33883
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 骨格筋Pin1は、運動機能及び糖代謝を制御する (2019)
  • Author(s): 中津 祐介、中井 菜摘、伊藤 輝、山本屋 武、上田 晃司、井上 賢紀、水野 優、味八木 茂、安達 伸生、櫛山 暁史、浅野 知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] SGLT2阻害薬によるマウス糖尿病性腎障害の改善及び、腎Pin1発現量の是正とAMPK活性化の関与 (2019)
  • Author(s): 井上 賢紀、中津 祐介、松永 泰花、山本屋 武、上田 晃司、井上 由貴、水野 優、櫛山 暁史、浅野 知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] 脂肪細胞のTrk-fused gene (TFG)による代謝制御機構の解明 (2019)
  • Author(s): 山本屋 武、長谷井 俊、中津 祐介、井上 賢紀、迫田 秀之、藤城 緑、櫛山 暁史、浅野 知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] キサンチンオキシターゼ阻害薬febuxostatによる糖尿病性腎症の改善とその作用機序の解明 (2019)
  • Author(s): 水野 優、中津 祐介、山本屋 武、上田 晃司、井上 賢紀、藤城 緑、迫田 秀之、櫛山 暁史、浅野 知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] Pin1 and Trk-fused gene (TFG): novel regulators for beta-cell mass and function (2019)
  • Author(s): 山本屋 武、中津 祐介、櫛山 暁史、石原 寿光、浅野 知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] SGLT2阻害薬によるマウス糖尿病性腎症の改善及び、腎Pin1発現量の是正とAMPK活性化の関与 (2018)
  • Author(s): 井上賢紀、中津祐介、松永泰花、山本屋武、上田晃嗣、井上由貴、櫛山暁史、浅野知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] マクロファージにおける糖代謝による活性酸素産生とインスリン抵抗性 (2018)
  • Author(s): 櫛山暁史、菊池貴子、迫田秀之、藤城緑、山本屋武、山崎広貴、中津祐介、浅野知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] プロリン異性化酵素Pin1による脂肪蓄積制御機構の解明 (2018)
  • Author(s): 中津祐介、山本屋武、上田晃嗣、井上賢紀、井上由貴、櫛山暁史、浅野知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] 2型糖尿病を対象としたキサンチン酸化還元酵素の血管合併症発症および進展に対する影響に関する探索研究 (2018)
  • Author(s): 藤城緑、櫛山暁史、山口賢、渡辺健太郎、江頭富士子、岡本真由美、村瀬貴代、中村敬志、山本屋武、中津祐介、浅野知一郎、石原寿光
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] Trk-fused gene (TFG)の糖代謝調節における役割の解明 (2018)
  • Author(s): 山本屋武、中津祐介、上田晃嗣、井上賢紀、迫田秀之、藤城緑、櫛山暁史、石原寿光、浅野知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会