Christ-Crain Mirjam, Kola Blerina, Lolli Francesca, Fekete Csaba, Seboek Dalma, Wittmann Gábor, Feltrin Daniel, Igreja Susana C, Ajodha Sharon, Harvey-White Judith, Kunos George, Müller Beat, Pralong Francois, Aubert Gregory, Arnaldi Giorgio, Giacchetti Gilberta, Boscaro Marco, Grossman Ashley B, Korbonits Márta
Department of Endocrinology, William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine, London EC1M 6BQ, UK.
FASEB J. 2008 Jun;22(6):1672-83. doi: 10.1096/fj.07-094144. Epub 2008 Jan 15.
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.
因药物治疗或库欣综合征导致的长期糖皮质激素暴露会引发胰岛素抵抗、中心性肥胖以及与代谢综合征相似的症状。我们推测，皮质类固醇的主要代谢作用是由关键代谢酶单磷酸腺苷激活蛋白激酶（AMPK）活性的变化介导的。已知激活AMPK会刺激下丘脑的食欲，并刺激外周的分解代谢过程。我们评估了糖皮质激素过量大鼠模型的下丘脑、肝脏、脂肪组织和心脏中AMPK的活性以及几种代谢酶的表达，同时还进行了体外研究，使用原代人脂肪细胞、原代大鼠下丘脑细胞培养物以及用地塞米松和二甲双胍处理的人肝癌细胞系。糖皮质激素处理抑制了大鼠脂肪组织和心脏中的AMPK活性，同时刺激了肝脏和下丘脑中的AMPK活性。在原代脂肪细胞和下丘脑细胞以及肝细胞系的体外研究中也观察到了类似的数据。二甲双胍是一种已知的AMPK调节剂，可预防皮质类固醇对人脂肪细胞和大鼠下丘脑神经元中AMPK的诱导作用。我们的数据表明，糖皮质激素诱导的AMPK变化构成了一种新机制，可解释食欲增加、内脏脂肪和肝脏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，二甲双胍治疗可能有效预防慢性糖皮质激素过量的代谢并发症。
