Pivotal Role of O-GlcNAc Modification in Cold-Induced Thermogenesis by Brown Adipose Tissue Through Mitochondrial Biogenesis

• Project/Area Number: 16K09743
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Satoshi Ugi 滋賀医科大学, 医学部, 講師 (20378483)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: O-GlcNAc修飾 / 褐色脂肪細胞 / 熱産生 / ミトコンドリア / 肥満 / 糖鎖修飾 / 褐色脂肪 / UCP1 / PGC-1α / エネルギー・糖質代謝異常

Outline of Final Research Achievements

The aim of study was to investigate the critical role of O-linked N-acetylglucosamine (O-GlcNAc ) modification in cold-induced thermogenesis. Deletion of Ogt in brown adipose tissue (BAT) resulted in severe cold intolerance with decreased Ucp1 expression. Furthermore, Ogt deletion led to decreased mitochondrial protein expression in conjunction with decreased PGC-1α protein expression, suggesting that O-GlcNAc modification in BAT is responsible for cold-induced thermogenesis. Hypothermia was significant under fasting conditions. This effect was mitigated after normal diet consumption but not after consumption of a ketogenic diet lacking carbohydrates, suggesting impaired diet-induced thermogenesis, particularly by fat. In conclusion, O-GlcNAc modification is essential for cold-induced thermogenesis and mitochondrial biogenesis in BAT. Glucose flux into BAT may be a signal to maintain BAT physiological responses.

Academic Significance and Societal Importance of the Research Achievements

褐色脂肪組織はマウスには存在するが成人では存在しないと最近まで考えられていたが、成人においても存在することが明らかになり、大きな注目を浴びている。本研究により、O-GlcNAc修飾が、褐色脂肪において、ミトコンドリアバイオジェネシスを介して熱産生を調節していることが明らかになった。このことから、O-GlcNAc修飾を調節することにより、褐色脂肪細胞を活性化させ、熱産生を増加させることにより、肥満の予防、治療法の開発につながる可能性がある。

Research Products

• [Journal Article] Lack of O-GlcNAcylation enhances exercise-dependent glucose utilization potentially through AMP-activated protein kinase activation in skeletal muscle. (2018)
  • Author(s): Murata K, Morino K, Ida S, Ohashi N, Lemecha M, Park SY, Ishikado A, Kume S, Choi CS, Sekine O, Ugi S, Maegawa H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 495 Pages: 2098-2140
  • Peer Reviewed / Open Access
• [Journal Article] MiR-494-3p regulates mitochondrial biogenesis and thermogenesis through PGC1-α signalling in beige adipocytes (2018)
  • Author(s): Lemecha Mengistu、Morino Katsutaro、Imamura Takeshi、Iwasaki Hirotaka、Ohashi Natsuko、Ida Shogo、Sato Daisuke、Sekine Osamu、Ugi Satoshi、Maegawa Hiroshi
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 15096-15096
  • DOI: 10.1038/s41598-018-33438-3
  • Peer Reviewed / Open Access
• [Journal Article] Pivotal Role of O -GlcNAc Modification in Cold-Induced Thermogenesis by Brown Adipose Tissue Through Mitochondrial Biogenesis (2017)
  • Author(s): Ohashi Natsuko、Morino Katsutaro、Ida Shogo、Sekine Osamu、Lemecha Mengistu、Kume Shinji、Park Shi-Young、Choi Cheol Soo、Ugi Satoshi、Maegawa Hiroshi
  • Journal Title: Diabetes Volume: 66 Issue: 9 Pages: 2351-2362
  • DOI: 10.2337/db16-1427
  • Peer Reviewed / Open Access
• [Presentation] 骨格筋におけるO-GlcNAc修飾の低下はAMPK蛋白発現の増加を伴う抗糖尿病および抗肥満作用を有する (2018)
  • Author(s): 村田 幸一郎, 森野 勝太郎, 井田 昌吾, 大橋 夏子, Lemecha Mengistu, Park Shi-Young, 石角 篤, 久米 真司, Choi Cheol Soo, 関根 理, 卯木 智, 前川 聡
  • Organizer: 第61回日本糖尿病学会総会
• [Presentation] miR-494 Regulates Mitochondrial Biogenesis and Thermogenesis through PGC1-α Signaling in Beige Adipocytes (2018)
  • Author(s): Mengistu lemecha
  • Organizer: The Annual meeting of 78th American diabetes association
  • Int'l Joint Research
• [Presentation] 褐色脂肪組織のO-GlcNAc修飾は寒冷環境における熱産生に重要である (2017)
  • Author(s): 大橋 夏子, 森野 勝太郎, 井田 昌吾, Mengistu Lemecha, 久米 真司, 関根 理, Park Shi-Young, Soo Choi Cheol, 卯木 智, 前川 聡
  • Organizer: 第38回日本肥満学会
• [Presentation] 褐色脂肪組織のO-GlcNAc修飾は寒冷環境における熱産生に重要である (2017)
  • Author(s): 大橋 夏子, 森野 勝太郎, 井田 昌吾, 関根 理, Lemecha Mengistu, 久米 真司, Park Shi-Young, Choi Cheol Soo, 卯木 智, 前川 聡
  • Organizer: 第60回日本糖尿病学会
• [Presentation] Metabolic switch by O-GlcNAcylation is essential for cold-induced thermogenesis in brown adipose tissue (2017)
  • Author(s): Natsuko Ohashi, Katsutaro Morino, Shogo Ida, Mengistu Lemecha, Shinji Kume, Osamu Sekine, Shi-Young Park, Cheol Soo Choi Satoshi Ugi1and Hiroshi Maegawa
  • Organizer: The Annual meeting of 77th American diabetes association 2017
  • Int'l Joint Research
• [Presentation] The pivotal role of O-GlcNAcylation in cold-induced thermogenesis by brown adipose tissue (2017)
  • Author(s): N. Ohashi, K. Morino, S. Ida, O. Sekine, M. Lemecha, S. Kume, S.-Y. Park, C.S. Choi, S. Ugi, H. Maegawa
  • Organizer: EASD2017
  • Int'l Joint Research
• [Presentation] 褐色脂肪組織におけるO-GlcNAc修飾は体温維持に重要である (2016)
  • Author(s): 大橋 夏子, 森野 勝太郎, 井田 昌吾, 久米 真司, 関根 理, 卯木 智, 前川 聡
  • 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