Mechanisms of exercise-induced alterations in the hypothalamo-pituitary adrenal axis activity

运动引起的下丘脑-垂体肾上腺轴活动改变的机制

• 批准号: 261306-2008
• 负责人: Riddell, Michael
• 金额: $ 2.55万
• 依托单位: York University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=504179
• 关键词: Mechanisms; exercise; induced; alterations; hypothalamo

Glucocorticoids are naturally occurring hormones that have several functions within the body, which include control of blood sugar levels, mobilization of fat and protein stores and immune suppression. During periods of stress, the Hypothalamo-Pituitary-Adrenal (HPA) axis releases high levels of glucocorticoids that prepare the organism for defence. Chronic elevations in glucocorticoids are undesirable, however, and appear to be linked to a number of immune, growth, neurological and metabolic disorders. As such, glucocorticoids must be tightly regulated within the body via specific glucocorticoid receptors in the brain and pituitary gland (i.e. negative feedback) and by enzymes in the various target tissues (e.g. fat, muscle and liver) that can either activate or inactivate local glucocorticoids. Poor regulation of glucocorticoids and chronic elevations in HPA activity are thought to be critical in the development of a common clinical condition called the Metabolic Syndrome (insulin resistance, high blood glucose, central obesity and high blood pressure), although the exact mechanism for this is unclear. Paradoxically, regular exercise, which is a potent activator of the HPA activity, is beneficial in preventing or improving many of these metabolic disorders. My laboratory is interested in determining if regular exercise (i.e. training) influences: 1) basal HPA activity; 2) HPA feedback sensitivity and; 3) local glucocorticoid activation. Moreover, we are particularly interested if some of the preventative effects of regular exercise on the development of the Metabolic Syndrome are via alterations in the HPA axis. We have recently shown that short term exercise behaviour increases resting HPA activity, while long term training causes a reduction in basal activity in healthy rodents. These adaptations appear to be mediated by changes in the gene expression of key regulatory proteins in the brain and pituitary gland as well as by changing the adrenal gland sensitivity to produce glucocorticoids. We are now interested in elucidating the molecular mechanisms for central and peripheral HPA adaptation to training and to explore the links between exercise, HPA activity and disease prevention.

糖皮质激素是天然存在的激素，在体内具有多种功能，包括控制血糖水平，动员脂肪和蛋白质储存以及免疫抑制。在应激期间，下丘脑-肾上腺皮质-肾上腺（HPA）轴释放高水平的糖皮质激素，为机体防御做好准备。然而，糖皮质激素的慢性升高是不希望的，并且似乎与许多免疫、生长、神经和代谢紊乱有关。因此，糖皮质激素必须在体内通过脑和脑垂体中的特定糖皮质激素受体（即负反馈）以及通过各种靶组织（例如脂肪、肌肉和肝脏）中的酶进行严格调节，这些酶可以激活或抑制局部糖皮质激素。糖皮质激素的调节不良和HPA活性的慢性升高被认为在称为代谢综合征（胰岛素抵抗、高血糖、向心性肥胖和高血压）的常见临床病症的发展中至关重要，尽管其确切机制尚不清楚。巧合的是，经常锻炼，这是一个有效的激活剂的HPA活动，是有益的，在预防或改善许多这些代谢紊乱。我的实验室感兴趣的是确定定期运动（即训练）是否影响：1）基础HPA活性; 2）HPA反馈敏感性; 3）局部糖皮质激素激活。此外，我们特别感兴趣的是，定期运动对代谢综合征发展的一些预防作用是否是通过HPA轴的改变。我们最近表明，短期运动行为增加休息HPA活动，而长期训练导致健康啮齿动物的基础活动减少。这些适应似乎是通过改变大脑和脑垂体中关键调节蛋白的基因表达以及改变肾上腺产生糖皮质激素的敏感性来介导的。我们现在有兴趣阐明中枢和外周HPA适应训练的分子机制，并探索运动，HPA活性和疾病预防之间的联系。