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，这与运动刺激的代谢事件有关，如葡萄糖运输，脂肪酸氧化和胰岛素敏感性。AMPK在代谢应激反应中被激活，如收缩、缺氧和氧化磷酸化的抑制。在本研究中，我们假设急性氧化应激刺激骨骼肌AMPK。我们的数据表明，氧化应激通过不依赖amp的机制激活骨骼肌中的alpha1，而不是alpha2，并导致葡萄糖转运速率和乙酰辅酶a羧化酶（ACC）磷酸化速率的增加。肌肉收缩激活alpha2，但这种激活可能发生在alpha1激活或不激活的情况下，这表明alpha2是负责收缩诱导代谢事件的主要亚型。在这项研究中，我们发现1)AMPK α 1是主要的异构体，在低强度收缩肌中，AMPK α 1被更多的amp独立磷酸化激活，2)AMPK α 2在高强度收缩肌中被amp依赖机制激活，3)每种异构体的激活都增强了骨骼肌中葡萄糖转运和ACC磷酸化。我们之前报道过，在肝脏中过表达瘦素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比目鱼中慢性增强，同时组织甘油三酯降低。尽管先前存在高瘦素血症，高脂肪饮食（HFD）喂养的LepTg发展为肥胖，胰岛素抵抗和高脂血症。与此同时，常规饮食喂养LepTg组的比目鱼AMPK升高被减弱，而给予HFD组的组织甘油三酯升高。用常规饮食替代HFD可使LepTg患者比目鱼肌AMPK强劲恢复，体重减轻率更高，胰岛素敏感性恢复。我们得出结论，在饮食改变的情况下，比目鱼AMPK在瘦素中的变化与其胰岛素敏感性平行，这表明骨骼肌AMPK活性与瘦素敏感性之间存在密切关联。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