Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo
Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo
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DOI：
10.1016/j.bbrc.2003.12.120
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发表时间：
2004-02-06
影响因子：
3.1
通讯作者：
Ruderman, NB
中科院分区：
文献类型：
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作者：
Saha, AK;Avilucea, PR;Ruderman, NB
噻唑烷二酮类化合物已被证明能激活培养细胞中AMP激活的蛋白激酶活性。它们在体内是否有类似的影响，如果是的话，是否在生理上相关尚不清楚。为了评估这些问题，我们研究了口服吡格列酮对大鼠肝脏和脂肪组织中AMPK磷酸化(AMPK-P)(一种衡量其活性的指标)、乙酰辅酶A羧化酶(ACC)活性和丙二酰辅酶A浓度的影响。在第一项研究中，对盐敏感大鼠(Dahl-S)进行了测量，这是一种患有内源性高甘油三酯血症和高水平丙二酰辅酶A的SD大鼠，经吡格列酮恢复到对照组水平。吡格列酮(20 mg/kgbw/d，连续3周)对对照组大鼠的P-AMPK和P-ACC(与ACC活性成反比)均无显著影响。然而，在Dahl-S大鼠中，AMPK-P和Acc-P的值比对照组低50%，经吡格列酮治疗后，两者的值增加了一倍。在第二项研究中，对Wistar大鼠口服吡格列酮(3 mg/kg体重/天)两周的疗效进行了评估。在基础状态下(无动物操纵)，吡格列酮使AMPK磷酸化增加一倍，并使ACC活性和肝脏丙二酰辅酶A浓度降低50%。正常血糖-高胰岛素钳夹(6h)后，肝脏和脂肪组织中AMPK和ACC的磷酸化水平下降了50%(表明其活性增加)，丙二酰辅酶A浓度也相应增加。在这两个组织中，吡格列酮的预处理阻止了这些变化。在基础状态下的Wistar大鼠中，用吡格列酮治疗后，肝脏中的ATP浓度降低1/3，ADP和AMP浓度升高。结果表明，在各种情况下，吡格列酮均能提高大鼠肝脏和脂肪组织中AMPK的活性。他们还提出，AMPK的这种激活可能是通过细胞能量状态的变化来调节的。吡格列酮的这些作用是否有助于其体内的胰岛素增敏和其他作用仍有待确定。(C)2003 Elsevier Inc.保留所有权利。
Thiazolidinediones have been shown to activate AMP-activated protein kinase activity in cultured cells. Whether they have a similar effect in vivo and if so whether it is physiologically relevant is not known. To assess these questions, we examined the effects of pioglitazone, administered orally to intact rats, on AMPK phosphorylation (AMPK-P) (a measure of its activation) and acetyl CoA carboxylase (ACC) activity and malonyl CoA concentration in rat liver and adipose tissue. In the first study, measurements were made in the DahI-salt-sensitive rat (Dahl-S), a strain of Sprague-Dawley rat with endogenous hypertriglyceridemia and high levels of malonyl CoA that are restored to control values by pioglitazone. Treatment with pioglitazone (20 mg/kg bw/day for 3 weeks) did not significantly increase either P-AMPK or P-ACC (which varies inversely with ACC activity) in control rats. However, in the Dahl-S rats values for AMPK-P and ACC-P were 50% lower than in control rats and were doubled by pioglitazone treatment. In a second study, the effects of two weeks treatment with pioglitazone (3 mg/kg bw/day administered orally) were evaluated in Wistar rats. Under basal conditions (no manipulation of the animals), pioglitazone increased AMPK phosphorylation by twofold and decreased ACC activity and the concentration of malonyl CoA by 50% in liver. Following a euglycemic-hyperinsulinemic clamp (6 h), 50% decreases in AMPK and ACC phosphorylation (indicating an increase in its activity) and comparable increases in malonyl CoA concentration were observed in liver and adipose tissue. In both tissues, pre-treatment with pioglitazone prevented these changes. Where studied (in Wistar rats under basal conditions) treatment with pioglitazone decreased the concentration of ATP by 1/3 and increased the concentration of ADP and AMP in liver. The results indicate that treatment with pioglitazone can increase AMPK activity in rat liver and adipose tissue in a variety of circumstances. They also suggest that this activation of AMPK may be mediated by a change in cellular energy state. Whether these effects of pioglitazone contribute to its insulin-sensitizing and other actions in vivo remains to be determined. (C) 2003 Elsevier Inc. All rights reserved.