Elucidation of the molecular mechanism of muscle insulin resistance induced by physical inactivity and establishment of prevention method.

• Project/Area Number: 15K01729
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• Research Institution: Juntendo University
• Principal Investigator: KAKEHI saori 順天堂大学, 医学(系)研究科(研究院), 特任助教 (00450560)
• Co-Investigator(Kenkyū-buntansha): 桜庭 景植 順天堂大学, スポーツ健康科学部, 教授 (50175460)
• Co-Investigator(Renkei-kenkyūsha): TAMURA Yoshifumi 順天堂大学, 医学部, 准教授 (80420834)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 不活動 / 骨格筋 / インスリン感受性 / 細胞内脂質 / 骨格筋細胞内脂質

Outline of Final Research Achievements

Physical inactivity (PI) has been shown to impair muscle insulin sensitivity (M-IS); however, its mechanisms have not been elucidated yet. To elucidate them, we used 24h hind-limb cast immobilization (HCI) for PI model in mice. We found that 24h HCI increased intramyocellular diacylglycerol (IMDG), while IM triacylglycerol (TG) was not changed. In parallel with IMDG accumulation, M-IS and insulin signaling were reciprocally impaired. The IMDG accumulations were also accompanied by increased expression level and activity of Lipin1, an enzyme converting phosphatidate to DG. The HCI induced IMDG accumulation and impaired M-IS in soleus muscle were prevented by dominant negative Lipin1 overexpression in the muscle. Finally, we found the possibility that 24h HCI in human also induce IMDG accumulation and Lipin1 expression. These results suggested that 24h HCI increase IMDG and decrease M-IS. Increased Lipin1 activity is at least partly involved in the mechanisms.

Research Products

• [Journal Article] Long-term, but not short-term high-fat diet induces fiber composition changes and impaired contractile force in mouse fast-twitch skeletal muscle (2017)
  • Author(s): Eshima H,Tamura Y, Kakehi S, Kurebayashi N, Murayama T, Nakamura K, Kakigi R,Okada T,Sakurai T, Kawamori R, Watada H
  • Journal Title: Physiological reports Volume: 5 Issue: 7 Pages: e13250-e13250
  • DOI: 10.14814/phy2.13250
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Correlates of insulin clearance in apparently healthy non-obese Japanese men. (2017)
  • Author(s): Kaga H, Tamura Y, Takeno K, Kakehi S, Funayama T, Furukawa Y, Nishitani-Yokoyama M, Shimada K, Daida H, Aoki S, Giacca A, Kanazawa A, Kawamori R, Watada H.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 1462-1462
  • DOI: 10.1038/s41598-017-01469-x
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Effects of alcohol abstinence on glucose metabolism in Japanese men with elevated fasting glucose: A pilot study. (2017)
  • Author(s): Funayama T, Tamura Y, Takeno K, Kawaguchi M, Kakehi S, Watanabe T, Furukawa Y, Kaga H, Yamamoto R, Kanazawa A, Fujitani Y, Kawamori R, Watada H.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 40277-40277
  • DOI: 10.1038/srep40277
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Relation Between Insulin Sensitivity and Metabolic Abnormalities in Japanese Men With BMI of 23-25 kg/m2. (2016)
  • Author(s): Takeno K, Tamura Y, Kawaguchi M, Kakehi S, Watanabe T, Funayama T, Furukawa Y, Kaga H, Yamamoto R, Kim M, Nishitani-Yokoyama M, Shimada K, Daida H, Aoki S, Taka H, Fujimura T, Sawada SS, Giacca A, Kanazawa A, Fujitani Y, Kawamori R, Watada H.
  • Journal Title: J Clin Endocrinol Metab Volume: 101 Pages: 3676-3684
  • Peer Reviewed
• [Journal Article] A randomized controlled trial of 130 g/day low-carbohydrate diet in type 2 diabetes with poor glycemic control. (2016)
  • Author(s): Sato J, Kanazawa A, Makita S, Hatae C, Komiya K, Shimizu T, Ikeda F, Tamura Y, Ogihara T, Mita T, Goto H, Uchida T, Miyatsuka T, Takeno K, Shimada S, Ohmura C, Watanabe T, Kobayashi K, Miura Y, Iwaoka M, Hirashima N, Fujitani Y, Watada H.
  • Journal Title: Clin Nutr Volume: 16 Issue: 4 Pages: 30169-8
  • DOI: 10.1016/j.clnu.2016.07.003
  • Peer Reviewed
• [Journal Article] Increased intramyocellular lipid/impaired insulin sensitivity is associated with altered lipid metabolic genes in muscle of high responders to a high-fat diet. (2016)
  • Author(s): Kakehi S, Tamura Y, Takeno K, Sakurai Y, Kawaguchi M, Watanabe T, Funayama T, Sato F, Ikeda S, Kanazawa A, Fujitani Y, Kawamori R, Watada H.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 310 Issue: 1 Pages: 32-40
  • DOI: 10.1152/ajpendo.00220.2015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TBC1D4/AS160のSNPは骨格筋インスリン抵抗性、2型糖尿病を規定する (2015)
  • Author(s): 筧 佐織、田村 好史
  • Journal Title: 内分泌・糖尿病・代謝内科 Volume: 41 Pages: 59-62
  • NAID: 40020553974
• [Presentation] Effects of exercise intensity on the insulin sensitivity and lipid composition in skeletal muscle under the same calorie consumption exercise. (2017)
  • Author(s): Saori Kakehi, Yoshifumi Tamura, Takashi Funayama, Kageumi Takeno, Ryuzo Kawamori and Hirotaka Watada
  • Organizer: Cell simposia Exercises metabolism
  • Int'l Joint Research
• [Presentation] Effects of exercise intensity on the insulin sensitivity and lipid composition in skeletal muscle under the same calorie consumption exercise. (2017)
  • Author(s): Saori Kakehi, Yoshifumi Tamura, Takashi Funayama, Kageumi Takeno, Ryuzo Kawamori and Hirotaka Watada
  • Organizer: The 3rd congress International academy of sportology
  • Int'l Joint Research
• [Presentation] Physical inactivity and high fat diet additively induce diacylglycerol accumulation and insulin resistance in muscle (2016)
  • Author(s): Saori Kakehi, Yoshifumi Tamura, Shin-ichi Ikeda, Naoko Kaga, Ryuzo Kawamori, Hirotaka Wata
  • Organizer: 76th American Diabetes Association Scientific Sessions
  • Place of Presentation: New Orleans, Louisiana
  • Year and Date: 2016-06-10
  • Int'l Joint Research
• [Presentation] 高脂肪食・不活動による骨格筋インスリン抵抗性発生メカニズム (2016)
  • Author(s): 筧 佐織
  • Organizer: 第59回日本糖尿尿病学会年次学術集会シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2016-05-19
  • Invited
• [Presentation] 高脂肪・不活動による骨格筋インスリン抵抗性惹起メカニズム (2015)
  • Author(s): 筧 佐織、田村 好史、池田 真一、加賀 直子、河盛 隆造、綿田 裕孝
  • Organizer: 分子糖尿病学シンポジウム
  • Place of Presentation: 東京都千代田区、丸ビルホール&コンファレンススクエア
  • Year and Date: 2015-12-05
• [Presentation] 24時間の脚ギプス固定は、骨格筋細胞内のジアシルグリセロールを増加させ、インスリン抵抗性を惹起する (2015)
  • Author(s): 筧 佐織、田村 好史、池田 真一、河盛 隆造、綿田 裕孝
  • Organizer: 第70回体力医学会大会
  • Place of Presentation: 和歌山県和歌山市、和歌山県民文化会館
  • Year and Date: 2015-09-18
• [Presentation] Intramyocellular lipid accumulation after high-fat diet is associated with the gene expression involved in lipid metabolism in skeletal muscle of non-obese men (2015)
  • Author(s): Kakehi S, Tamura Y, Takeno K, Sakurai Y, Kawaguchi M, Watanabe T, Funayama T, Sato F, Ikeda S, Kanazawa A, Fujitani Y, Kawamori R, Watada H
  • Organizer: 2nd Congress, International Academy of Sportology.
  • Place of Presentation: 東京都文京区、順天堂大学
  • Year and Date: 2015-09-12
• [Presentation] Physical inactivity and high fat diet synergistically enhance the accumulation of intramyocellular diacylglycerol and induce insulin resistance in murine soleus muscle (2015)
  • Author(s): Kakehi S, Tamura Y, Kawamori R, Watada H
  • Organizer: Cell Symposia: Exercise Metabolism.
  • Place of Presentation: アムステルダム、オランダ
  • Year and Date: 2015-07-12
• [Presentation] Mechanisums of insulin resistance after 24hours physical inactivity in murine soleus muscle (2015)
  • Author(s): Kakehi S, Tamura Y, Ikeda S, Kawamori R, Watada H.
  • Organizer: 62nd Annual Meeting of American College of Sports Medicine.
  • Place of Presentation: サンディエゴ、アメリカ合衆国
  • Year and Date: 2015-05-26