AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing's syndrome
AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing's syndrome
复制标题
DOI：
10.1096/fj.07-094144
复制
发表时间：
2008-06-01
期刊：
影响因子：
4.8
通讯作者：
Korbonits, Marta
中科院分区：
文献类型：
--
作者：
Christ-Crain, Mirjam;Kola, Blerina;Korbonits, Marta
长期接触糖皮质激素，无论是药物治疗还是库欣综合征，都会导致胰岛素抵抗、中心性肥胖和类似代谢综合征的症状。我们假设皮质类固醇的主要代谢作用是通过关键代谢酶一磷酸腺苷活化蛋白激酶(AMPK)活性的变化来调节的。众所周知，激活AMPK可以刺激下丘脑的食欲，并刺激外周的分解代谢过程。我们评估了糖皮质激素过多模型大鼠下丘脑、肝脏、脂肪组织和心脏中AMPK的活性和几种代谢酶的表达，以及使用原代人类脂肪和原代大鼠下丘脑细胞培养的体外研究，以及地塞米松和二甲双胍处理的人肝癌细胞株。糖皮质激素治疗抑制了大鼠脂肪组织和心脏中的AMPK活性，而刺激了肝脏和下丘脑中的AMPK活性。在体外，在初级脂肪细胞、下丘脑细胞和肝细胞系中也观察到了类似的数据。已知的AMPK调节剂二甲双胍可阻止糖皮质激素对人脂肪细胞和大鼠下丘脑神经元AMPK的影响。我们的数据表明，糖皮质激素诱导的AMPK变化构成了一种新的机制，可以解释食欲增加、内脏脂肪和肝组织中脂质沉积以及心脏变化，这些都是糖皮质激素过量的特征。我们的数据表明，二甲双胍治疗可以有效地预防慢性糖皮质激素过量的代谢并发症。
Chronic exposure to glucocorticoid hormones, resulting from either drug treatment or Cushing's syndrome, results in insulin resistance, central obesity, and symptoms similar to the metabolic syndrome. We hypothesized that the major metabolic effects of corticosteroids are mediated by changes in the key metabolic enzyme adenosine monophosphate-activated protein kinase (AMPK) activity. Activation of AMPK is known to stimulate appetite in the hypothalamus and stimulate catabolic processes in the periphery. We assessed AMPK activity and the expression of several metabolic enzymes in the hypothalamus, liver, adipose tissue, and heart of a rat glucocorticoid- excess model as well as in in vitro studies using primary human adipose and primary rat hypothalamic cell cultures, and a human hepatoma cell line treated with dexamethasone and metformin. Glucocorticoid treatment inhibited AMPK activity in rat adipose tissue and heart, while stimulating it in the liver and hypothalamus. Similar data were observed in vitro in the primary adipose and hypothalamic cells and in the liver cell line. Metformin, a known AMPK regulator, prevented the corticosteroid-induced effects on AMPK in human adipocytes and rat hypothalamic neurons. Our data suggest that glucocorticoid-induced changes in AMPK constitute a novel mechanism that could explain the increase in appetite, the deposition of lipids in visceral adipose and hepatic tissue, as well as the cardiac changes that are all characteristic of glucocorticoid excess. Our data suggest that metformin treatment could be effective in preventing the metabolic complications of chronic glucocorticoid excess.