The Role of AMP kinase in Exercise-Stimulated Insulin Sensitivity in Skeletal Muscle

AMP 激酶在骨骼肌运动刺激胰岛素敏感性中的作用

• 批准号: 15500441
• 负责人: HAYASHI Tatsuya
• 金额: $ 2.37万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15500441/
• 关键词: skeletal muscle; exercise; insulin sensitivity; AMP kinase; muscle contraction; signal transduction; glucose metabolism; leptin; トレーニング

1.Skeletal muscle expresses two catalytic subunits, alpha1 and alpha2, of the 5'-AMP-activated protein kinase (AMPK), which is implicated in exercise-stimulated metabolic events, such as glucose transport, fatty acid oxidation and insulin sensitivity. AMPK is activated in response to metabolic stresses, such as contraction, hypoxia, and the inhibition of oxidative phosphorylation. In this research we hypothesized that acute oxidative stress stimulates AMPK in skeletal muscle. Our data suggest that oxidative stress activates alpha1, but not alpha2, in skeletal muscle via an AMP-independent mechanism and leads to increases in the rate of glucose transport and acetyl CoA carboxylase (ACC) phosphorylation.2.Muscle contraction activates alpha2, but this activation may occur with or without activation of alpha1, suggesting that alpha2 is the major isoform responsible for contraction-induced metabolic events. In this research we found that 1)AMPK alpha1 is the predominant isoform activated by … More AMP-independent phosphorylation in low-intensity contracting muscle, 2)AMPK alpha2 is activated by an AMP-dependent mechanism in high-intensity contracting muscle, and 3)activation of each isoform enhances glucose transport and ACC phosphorylation in skeletal muscle.3.We previously reported that transgenic mice overexpressing leptin in the liver (LepTg) exhibit hyperleptinemia and enhanced insulin sensitivity. In this research we found that phosphorylation of AMPK was chronically augmented in LepTg soleus, with a concomitant decrease in tissue triglyceride. Despite preexisting hyperleptinemia, high-fat diet (HFD)-fed LepTg developed obesity, insulin-resistance, and hyperlipidemia. In parallel, elevated soleus AMPK in regular diet-fed LepTg was attenuated, and tissue triglyceride was increased in those given HFD. Substitution of HFD with regular diet caused a robust recovery of soleus AMPK in LepTg, with a higher rate of body weight reduction and a regain of insulin sensitivity. We conclude that soleus AMPK in LepTg changes in parallel with its insulin sensitivity under dietary modification, suggesting a close association between skeletal muscle AMPK activity and sensitivity to leptin. Less

1.骨骼肌肉表达了5'AMP激活的蛋白激酶（AMPK）的两个催化亚基，Alpha1和alpha2，它们在运动刺激的代谢事件中实施，例如葡萄糖转运，脂肪酸氧化和胰岛素敏感性。 AMPK因代谢应激而激活，例如收缩，缺氧和氧化磷酸化的抑制。在这项研究中，我们假设急性氧化应激会刺激骨骼肌中的AMPK。我们的数据表明，氧化应激通过非AMP独立的机制激活骨骼肌中的α1，但不能激活α2，导致葡萄糖传输速率和乙酰基CoA羧化酶（ACC）磷酸化的速率增加。2.Musclic.2.Musclus Contraction。合同引起的代谢事件。在这项研究中，我们发现1）AMPK alpha1是……在低强度收缩肌肉中更依赖AMP的磷酸化激活的主要同工型，2）AMPK alpha2被AMP依赖性机制激活，由AMP依赖性机制在高强度的肌肉中，并在每种Isof肌肉中均可增强glcool usef usef glcood use 3. glcook usce 3. sproscration 3.转基因小鼠过表达肝脏（LEPTG）暴露的高血治血症并增强胰岛素敏感性。在这项研究中，我们发现AMPK的磷酸化在LeptG的比目鱼中长期增强，随之而来的甘油三酸酯伴随降低。尽管已经存在高脂蛋白血症，但高脂饮食（HFD）饮食仍会促进肥胖，胰岛素抵抗和高脂血症。同时，在常规饮食喂养的lettg中升高的比目鱼AMPK降低了，并且在给定的HFD中增加了甘油三酸酯。用常规饮食替换HFD会导致LEPTG中比目鱼AMPK的稳健恢复，体重减轻较高，并恢复胰岛素敏感性。我们包括lettG中的比目鱼AMPK在饮食修饰下并行变化与其胰岛素敏感性并行变化，这表明骨骼肌AMPK活性与对瘦素的敏感性之间存在密切的关联。

项目成果

Hamada T.: "Enhancement of whole body glucose uptake during and after human skeletal muscle low-frequency electrical stimulation"J Appl Physiol.. 94(6). 2107-2112 (2003)

Hamada T.：“人体骨骼肌低频电刺激期间和之后全身葡萄糖摄取的增强”J Appl Physiol.. 94(6)。

Toyoda T.: "Possible involvement of the α1 isoform of 5'AMP-activated protein kinase in oxidative-stress-stimulated glucose transport in skeletal muscle"Am J Physiol Endocrinol Metab.. (in press). (2004)

Toyoda T.：“5AMP 激活蛋白激酶的 α1 亚型可能参与骨骼肌氧化应激刺激的葡萄糖转运”Am J Physiol Endocrinol Metab..（出版中）。

CCAAT/enhancer binding protein alpha maintains the ability of insulin-stimulated GLUT4 translocation in 3T3-C2 fibroblastic cells.

CCAAT/增强子结合蛋白 α 维持 3T3-C2 成纤维细胞中胰岛素刺激的 GLUT4 易位的能力。

• 发表时间: 2005
• 期刊: Biochim Biophys Acta 1745 (1)
• 作者: Isogai;Hirohisa;磯貝浩久;Morishima M;Morishima M;Toyoda T;Kakui S;Toyoda T;Kanezaki Y;Fujimoto M
• 通讯作者: Fujimoto M

Association of Ob-R gene polymorphism and insulin resistance in Japanesemen.

Ob-R 基因多态性与日本男性胰岛素抵抗的关联。

• 发表时间: 2004
• 期刊: Metabolism 53(5)
• 作者: Matoba Hideki;Norisada N.;Morishima M;Fujimoto M.;Matoba Hideki;Takahashi-Yasuno A.
• 通讯作者: Takahashi-Yasuno A.

Possible involvement of the alpha1 isoform of 5'AMP-activated protein kinase in oxidative stress-stimulated glucose transport in skeletal muscle.

• DOI: 10.1152/ajpendo.00487.2003
• 发表时间: 2004-07
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: Taro Toyoda;Tatsuya Hayashi;Licht Miyamoto;S. Yonemitsu;M. Nakano;Satsuki Tanaka;K. Ebihara;H. Masuzaki;K. Hosoda;G. Inoue;A. Otaka;Kenji Sato;T. Fushiki;K. Nakao