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

1.骨骼肌表达5 '-AMP活化蛋白激酶（AMPK）的两个催化亚基α 1和α 2，其涉及运动刺激的代谢事件，如葡萄糖转运、脂肪酸氧化和胰岛素敏感性。AMPK响应于代谢应激而被激活，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刺激骨骼肌AMPK。我们的数据表明，氧化应激激活α 1，而不是α 2，在骨骼肌通过AMP-独立的机制，并导致葡萄糖转运和乙酰辅酶A羧化酶（ACC）磷酸化的速率增加。2.肌肉收缩激活α 2，但这种激活可能发生或没有激活的α 1，这表明α 2是主要的异构体负责收缩诱导的代谢事件。在这项研究中，我们发现1）AMPK α 1是主要的亚型， 关于我们 AMPK α 2在高强度肌肉收缩中通过AMP依赖性机制被激活; AMPK α 2和AMPK α 2的激活增强了骨骼肌中葡萄糖的转运和ACC的磷酸化。3.我们以前报道过在肝脏中过表达瘦素（LepTg）的转基因小鼠表现出高瘦素血症和胰岛素敏感性增强。在这项研究中，我们发现AMPK的磷酸化在LepTg比目鱼肌中长期增强，伴随着组织甘油三酯的减少。尽管预先存在高瘦素血症，高脂饮食（HFD）喂养的LepTg发展肥胖，胰岛素抵抗和高脂血症。与此同时，在常规饮食喂养的LepTg中升高的比目鱼肌AMPK被减弱，并且在给予HFD的那些中组织甘油三酯增加。用常规饮食替代HFD引起LepTg中比目鱼肌AMPK的稳健恢复，具有更高的体重减轻率和胰岛素敏感性的恢复。我们的结论是，比目鱼肌AMPK在LepTg的变化与其胰岛素敏感性的饮食调整下平行，这表明骨骼肌AMPK活性和对瘦素的敏感性之间存在密切联系。少

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