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首页> 外文期刊>American Journal of Physiology >Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues.
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Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues.

机译：噻唑烷二酮可以在哺乳动物组织中快速激活AMP激活的蛋白激酶。

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Thiazolidinediones (TZDs) are insulin-sensitizing agents used in the treatment of type 2 diabetes. A widely held view is that their action is secondary to transcriptional events that occur when TZDs bind to the nuclear receptor PPARgamma in the adipocyte and stimulate adipogenesis. It has been proposed that this increases insulin sensitivity, at least in part, by increasing the expression and release of adiponectin, an adipokine that activates the fuel-sensing enzyme AMP-activated protein kinase (AMPK). In this study, we report that TZDs also acutely activate AMPK in skeletal muscle and other tissues by a mechanism that is likely independent of PPARgamma-regulated gene transcription. Thus incubation of isolated rat EDL muscles in medium containing 5 microM troglitazone for 15 min (too brief to be attributable to transcription) significantly increased pAMPK and pACC. At a concentration of 100 microM, troglitazone maximally increased these parameters and caused twofold increases in 2-deoxy-d-glucose uptake and the oxidation of exogenous [(14)C]palmitate. Time course studies revealed that troglitazone-induced increases in pAMPK and pACC abundance at 15 min were paralleled by an increase in the AMP-to-ATP ratio and that by 60 min all of these parameters had returned to baseline values. Increases in pAMPK and pACC were also observed in skeletal muscle, liver, and adipose tissue in intact rats 15 min after the administration of a single dose of troglitazone (10 mg/kg, ip). Likewise, troglitazone and another TZD, pioglitazone, caused rapid increases in pAMPK and pACC of equal magnitude in Swiss 3T3 fibroblasts with and without sufficient PPARgamma to mediate the expression of target genes. The results indicate that TZDs can act within minutes to activate AMPK in mammalian tissues. They suggest that this effect is associated with a change in cellular energy state and that it is not dependent on PPARgamma-mediated gene transcription.
机译：噻唑烷二酮（TZD）是用于治疗2型糖尿病的胰岛素增敏剂。一种普遍的观点是，当TZD与脂肪细胞中的核受体PPARγ结合并刺激脂肪形成时，其作用是转录事件的继发作用。已经提出，这至少部分地通过增加脂联素的表达和释放来增加胰岛素敏感性，脂联素是激活燃料感测酶AMP激活的蛋白激酶（AMPK）的脂肪因子。在这项研究中，我们报告说TZDs还可能通过一种可能独立于PPARγ调节的基因转录的机制来急性激活骨骼肌和其他组织中的AMPK。因此，将分离的大鼠EDL肌肉在含有5 microM曲格列酮的培养基中孵育15分钟（时间太短，不能归因于转录）会显着增加pAMPK和pACC。在浓度为100 microM时，曲格列酮最大程度地增加了这些参数，并导致2-脱氧-d-葡萄糖摄取和外源[[14] C]棕榈酸的氧化增加了两倍。时程研究表明，曲格列酮诱导的15分钟内pAMPK和pACC丰度的增加与AMP与ATP比率的增加并存，并且到60分钟时所有这些参数均已恢复到基线值。服用曲格列酮单剂量（10 mg / kg，腹腔注射）15分钟后，在完整大鼠的骨骼肌，肝脏和脂肪组织中也观察到pAMPK和pACC的增加。同样，曲格列酮和另一种TZD吡格列酮在有或没有足够PPARγ介导靶基因表达的瑞士3T3成纤维细胞中引起pAMPK和pACC的大小均等迅速增加。结果表明，TZD可以在数分钟内起作用，以激活哺乳动物组织中的AMPK。他们认为这种作用与细胞能量状态的改变有关，并且它不依赖于PPARγ介导的基因转录。

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