Elucidation of tetrahydrobiopterin-induced BAT differentiation and regulation of glucose as well as energy metabolism

• Project/Area Number: 15K19514
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: Kyoto University
• Principal Investigator: Fujita Yoshihito 京都大学, 医学研究科, 助教 (50547809)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 褐色脂肪 / 糖尿病 / 肥満 / eNOS / 褐色脂肪組織

Outline of Final Research Achievements

Brown adipose tissue (BAT) is a central organ that acts to increase energy expenditure; its regulatory factors could be clinically useful in the treatment of obesity. Tetrahydrobiopterin (BH4) is an essential co-factor of tyrosine hydroxylase and nitric oxide synthase (NOS). Although BH4 regulates the known regulatory factors of BAT such as noradrenaline (NA) and nitric oxide (NO), participation of BH4 in BAT function remains unclear. We investigate the role of BH4 in the regulation of BAT. Hph-1 mice, a mouse model of BH4 deficiency, exhibit obesity, adiposity, glucose intolerance, insulin resistance, and impaired BAT function. By BAT transplantation from BH4-sufficient mice (control mice) into BH4-deficient mice, impaired BAT function was ameliorated together with systemic metabolic disturbances, strongly suggesting that BH4-induced BAT has a critical role in the regulation of systemic energy metabolism. Taken together, BH4 activates BAT and regulates systemic energy metabolism.

Research Products

• [Journal Article] Metformin: New Preparations and Non-Glycemic Benefits. (2017)
  • Author(s): Y. Fujita, N. Inagaki.
  • Journal Title: Curr Diab Rep. Volume: 17 Issue: 1 Pages: 1-10
  • DOI: 10.1007/s11892-017-0829-8
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Metformin: clinical topics and new mechanisms of action (2017)
  • Author(s): Y. Fujita, N. Inagaki.
  • Journal Title: Diabetol Int Volume: 8 Issue: 1 Pages: 4-6
  • DOI: 10.1007/s13340-016-0300-0
  • NAID: 40021131530
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of structured testing versus routine testing of blood glucose in diabetes self-management: A randomized controlled trial. (2017)
  • Author(s): A. Nishimura, SI. Harashima, Y. Fujita, D. Tanaka, Y. Wang, Y. Liu, N. Inagaki.
  • Journal Title: J Diabetes Complications. Volume: 31 Issue: 1 Pages: 228-233
  • DOI: 10.1016/j.jdiacomp.2016.08.019
  • NAID: 120005844237
  • Peer Reviewed
• [Journal Article] Sitagliptin monotherapy has better effect on insulinogenic index than glimepiride monotherapy in Japanese patients with type 2 diabetes mellitus: a 52-week, multicenter, parallel-group randomized controlled trial. (2016)
  • Author(s): Kondo Y, Harada N, Hamasaki A, Kaneko S, Yasuda K, Ogawa E, Harashima S, Yoneda H, Fujita Y, Kitano N, Nakamura Y, Matsuo F, Shinji M, Hinotsu S, Nakayama T, Inagaki N
  • Journal Title: Diabetol Metab Syndr. Volume: 8 Issue: 1 Pages: 1-5
  • DOI: 10.1186/s13098-016-0131-y
  • NAID: 120005758426
  • Peer Reviewed / Open Access
• [Journal Article] DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells. (2015)
  • Author(s): Obara A, Fujita Y, Abudukadier A, Fukushima T, Oguri Y, Ogura M, Harashima S, Hosokawa M, Inagaki N.
  • Journal Title: Biochem Biophys Res Commun. Volume: 460 Issue: 4 Pages: 1047-1052
  • DOI: 10.1016/j.bbrc.2015.03.148
  • Peer Reviewed / Open Access
• [Presentation] テトラヒドロビオプテリンによる褐色脂肪制御機構の解明 (2017)
  • Author(s): 小栗靖生、藤田義人、Abulizi Abdukadier、大橋晶子、後藤剛、古谷太志、小原章央、福島徹、松尾奈緒美、Kim Minji、細川雅也、河田照雄、長谷川宏幸、稲垣暢也
  • Organizer: 第31回日本糖尿病・肥満動物学会
  • Place of Presentation: 横浜
  • Year and Date: 2017-02-10
• [Presentation] テトラヒドロビオプテリンは褐色脂肪機能を活性化させ、全身の糖・エネルギー代謝を制御する (2017)
  • Author(s): 小栗靖生、藤田義人、Abulizi Abdukadier、大橋晶子、後藤剛、古谷太志、小原章央、福島徹、松尾奈緒美、Kim Minji、細川雅也、河田照雄、長谷川宏幸、稲垣暢也
  • Organizer: 第20回日本病態栄養学会
  • Place of Presentation: 京都
  • Year and Date: 2017-01-13
• [Presentation] テトラヒドロビオプテリンは褐色脂肪機能を活性化させ、全身のエネルギー・糖代謝を制御する (2016)
  • Author(s): 小栗靖生、藤田義人、Abulizi Abdukadier、大橋晶子、後藤剛、古谷太志、小原章央、福島徹、松尾奈緒美、Kim Minji、細川雅也、河田照雄、長谷川宏幸、稲垣暢也
  • Organizer: 第37回日本肥満学会
  • Place of Presentation: 東京
  • Year and Date: 2016-10-07
• [Presentation] テトラヒドロビオプテリンによる糖・脂質およびエネルギー代謝制御機構の解明 (2016)
  • Author(s): 藤田 義人,小栗 靖生,Abulizi Abdukadier,小原 章央,大橋 晶子,古谷 太志,松尾 奈緒美,福島 徹,長谷川 宏幸,細川 雅也,稲垣 暢也
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都
  • Year and Date: 2016-05-19
• [Presentation] eNOS補酵素テトラヒドロビオプテリンの糖尿病腎症発症機序への関与の解明 (2016)
  • Author(s): 小栗靖生、藤田義人、古谷太志、松尾奈緒美、屋山勝俊、小原章央、Abulizi Abdukadier、大橋晶子、長谷川宏幸、鶴山竜昭、細川雅也、稲垣暢也
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都
  • Year and Date: 2016-05-19
• [Presentation] テトラヒドロビオプテリンは褐色脂肪機能を活性化させ、全身の糖・エネルギー代謝を制御する (2016)
  • Author(s): 小栗靖生、藤田義人、Abulizi Abdukadier、大橋晶子、後藤剛、古谷太志、小原章央、福島徹、松尾奈緒美、Kim Minji、細川雅也、河田照雄、長谷川宏幸、稲垣暢也
  • Organizer: 第21回日本肥満学会アディポサイエンス・シンポジウム
  • Place of Presentation: 大阪
• [Presentation] Novel Role of eNOS Co-factor Tetrahydrobiopterin for Mitochondrial Regulation in Adiposity and Energy Homeostasis (2015)
  • Author(s): Oguri Y, Fujita Y, Abudukadier A, Obara A, Ohashi A, Furuya F, Fukushima T, Hasegawa H, Hosokawa M, Inagaki N.
  • Organizer: American Diabetes Association 75th Scientific Sessions.
  • Place of Presentation: Boston, USA
  • Year and Date: 2015-06-05
  • Int'l Joint Research
• [Presentation] テトラヒドロビオプテリンによる糖・脂質およびエネルギー代謝制御機構の解明 (2015)
  • Author(s): 小栗靖生、藤田義人、Abulizi Abdukadier、小原章央、大橋晶子、古谷太志、福島徹、長谷川宏幸、細川雅也、稲垣暢也.
  • Organizer: 第58回日本糖尿病学会年次学術集会/第2回肝臓と糖尿病・代謝研究会．
  • Place of Presentation: シーモールホール, 山口, 下関
  • Year and Date: 2015-05-21