Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues
Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues
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DOI：
10.1152/ajpendo.00453.2005
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发表时间：
2006-07-01
影响因子：
5.1
通讯作者：
Tomas, Eva
中科院分区：
文献类型：
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作者：
LeBrasseur, Nathan K.;Kelly, Meghan;Tomas, Eva
噻唑烷二酮类能快速激活哺乳动物组织中amp活化的蛋白激酶。[J] .中国生物医学工程学报，2006,31(1):379 - 379。首次出版于2006年2月7日；doi: 10.1152 / ajpendo。00453.2005.噻唑烷二酮类（TZDs）是用于治疗2型糖尿病的胰岛素增敏剂。一种被广泛接受的观点是，当TZDs与脂肪细胞中的核受体PPAR γ结合并刺激脂肪形成时，它们的作用是次要的转录事件。有人提出，这增加了胰岛素敏感性，至少部分是通过增加脂联素的表达和释放，脂联素是一种激活燃料感应酶amp活化蛋白激酶（AMPK）的脂肪因子。在这项研究中，我们报道TZDs还通过一种可能独立于PPAR γ调节基因转录的机制，急性激活骨骼肌和其他组织中的AMPK。因此，分离的大鼠EDL肌肉在含有5 μ M曲格列酮的培养基中孵育15分钟（时间太短，无法归因于转录），pAMPK和pACC显著增加。在100 μ M浓度下，曲格列酮最大限度地提高了这些参数，使2-去氧d -葡萄糖的摄取和外源[C-14]棕榈酸酯的氧化增加了两倍。时间过程研究显示，曲格列酮在15分钟诱导的pAMPK和pACC丰度的增加与AMP-to-ATP比率的增加是平行的，到60分钟时，所有这些参数都恢复到基线值。单剂量曲格列酮（10 mg/kg, ip）给药15分钟后，完整大鼠骨骼肌、肝脏和脂肪组织中pAMPK和pACC也有所增加。同样，曲格列酮和另一种TZD吡格列酮在有或没有足够的PPAR γ介导靶基因表达的情况下，都能引起瑞士3T3成纤维细胞中pAMPK和pACC的等量快速增加。结果表明，TZDs可以在几分钟内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变化有关，而不依赖于PPAR γ介导的基因转录。
Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues. Am J Physiol Endocrinol Metab 291: E175-E181, 2006. First published February 7, 2006; doi: 10.1152/ajpendo. 00453.2005.-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 PPAR gamma 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 PPAR gamma-regulated gene transcription. Thus incubation of isolated rat EDL muscles in medium containing 5 mu M troglitazone for 15 min (too brief to be attributable to transcription) significantly increased pAMPK and pACC. At a concentration of 100 mu M, troglitazone maximally increased these parameters and caused twofold increases in 2-deoxy-D-glucose uptake and the oxidation of exogenous [C-14] 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 PPAR gamma 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 PPAR gamma-mediated gene transcription.