The role of O-GlcNAcylation in the Glucose metabolism in Skeletal Muscle

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09744
• 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: Morino Katsutaro 滋賀医科大学, 医学部, 助教 (90444447)
• Co-Investigator(Kenkyū-buntansha): 今村 武史 鳥取大学, 医学部, 教授 (00552093)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 骨格筋 / AMPK / 糖代謝 / 加齢 / 肥満

Outline of Final Research Achievements

O-GlcNAcylation is a post-translational modification that is characterized by the addition of N-acetylglucosamine(GlcNAc) to proteins by O-GlcNAc transferase (Ogt). The degree of O-GlcNAcylation is thought to be associated with glucotoxicity and diabetic complications, because GlcNAc is produced by a branch of the glycolytic pathway. However, its role in skeletal muscle has not been fully elucidated. In　this study, we created skeletal muscle-specific Ogt knockout (Ogt-MKO) mice and analyzed their glucose metabolism. During an intraperitoneal glucose tolerance test, blood glucose was slightly lower in Ogt-MKO mice than in control Ogt-flox mice. High fat diet-induced obesity and insulin resistance were reversed in Ogt-MKO mice. In addition, 12-month-old Ogt-MKO mice had lower body mass with increased AMP-activated protein kinase a (AMPKa) protein expression. In conclusion, loss of O-GlcNAcylation facilitates glucose utilization in skeletal muscle, potentially through AMPK activation.

Free Research Field

糖尿病・肥満症

Academic Significance and Societal Importance of the Research Achievements

本研究結果より、O-GlcNAc修飾が骨格筋で起こらなくなると、血糖が低下し、体重が減少する事が分かった。Ogtノックアウトマウスは少なくとも1歳を超えて元気に過ごしており、目立った臓器障害も観察されなかったことから、糖尿病や肥満の新規治療ターゲットになる可能性がある。しかしながら、他の研究で脂肪細胞や膵β細胞でO-GlcNAc修飾がなくなると臓器障害を来して言うことから、骨格筋だけに薬剤が吸収されるようなドラッグデリバリー技術との組み合わせが必要となると考えられる。