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

糖皮质激素是一种自然产生的激素，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抑制免疫。在压力时期，下丘脑-垂体-肾上腺（HPA）轴释放高水平的糖皮质激素，为机体防御做准备。然而，糖皮质激素的慢性升高是不可取的，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大脑和脑垂体中的特定糖皮质激素受体（即负反馈）以及各种靶组织（例如脂肪，肌肉和肝脏）中的酶进行严格调节，这些酶可以激活或灭活局部糖皮质激素。糖皮质激素调节不良和HPA活性的慢性升高被认为是一种称为代谢综合征（胰岛素抵抗、高血糖、中枢性肥胖和高血压）的常见临床状况发展的关键，尽管其确切机制尚不清楚。矛盾的是，有规律的运动是HPA活性的有效激活剂，对预防或改善许多代谢紊乱是有益的。我的实验室有兴趣确定定期运动（即训练）是否会影响：1)基础HPA活动；2) HPA反馈灵敏度和；3)局部糖皮质激素激活。此外，我们特别感兴趣的是，如果定期运动对代谢综合征发展的一些预防作用是通过改变下丘脑轴。我们最近的研究表明，短期运动行为会增加静息时下丘脑活动，而长期训练会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对产生糖皮质激素的敏感性来介导的。我们现在感兴趣的是阐明中枢和外周HPA适应训练的分子机制，并探索运动、HPA活动和疾病预防之间的联系。

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.