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.骨骼肌表达 5'-AMP 激活蛋白激酶 (AMPK) 的两个催化亚基 alpha1 和 alpha2，这与运动刺激的代谢事件有关，例如葡萄糖转运、脂肪酸氧化和胰岛素敏感性。响应代谢应激（例如收缩、缺氧和氧化磷酸化的抑制）而被激活。在这项研究中，我们发现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 AMP 独立机制激活骨骼肌中的 α1，但不激活 α2，并导致葡萄糖转运和乙酰辅酶 A 羧化酶 (ACC) 磷酸化速率增加。2. 肌肉收缩激活 alpha2，但这种激活可能在 alpha1 激活或不激活的情况下发生，这表明 alpha2 是负责收缩诱导的代谢事件的主要亚型。 1)AMPK α1 是低强度收缩肌肉中由 AMP 独立磷酸化激活的主要亚型，2)AMPK α2 在高强度收缩肌肉中由 AMP 依赖性机制激活，3) 每种亚型的激活增强骨骼肌中的葡萄糖转运和 ACC 磷酸化。3.我们之前报道过肝脏中过度表达瘦素（LepTg）的转基因小鼠表现出在这项研究中，我们发现，LepTg 比目鱼肌中 AMPK 的磷酸化长期增强，同时组织甘油三酯也随之降低，但高脂肪饮食 (HFD) 喂养的 LepTg 却出现了肥胖和胰岛素抵抗。和高脂血症同时，常规饮食喂养的 LepTg 中比目鱼肌 AMPK 的升高有所减弱，组织中的升高也有所减弱。接受 HFD 的患者甘油三酯增加。用常规饮食替代 HFD 导致 LepTg 中的比目鱼肌 AMPK 强劲恢复，体重减轻率更高，并且胰岛素敏感性的恢复与 LepTg 中的比目鱼肌 AMPK 变化平行。饮食调整下的胰岛素敏感性较低，表明骨骼肌 AMPK 活性与瘦素敏感性之间存在密切关联。

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