Examining the mechanisms for the lipolytic and antilipolytic effects of glucocorticoids in adipose tissue

糖皮质激素(GC)是一种天然产生的类固醇激素，通过激活 下丘脑-垂体-肾上腺(HPA)轴在昼夜节律和压力时期(如运动或饥饿)。长期以来，皮质醇(人类)或皮质酮(啮齿动物)等GCs一直被认为在能量需求可能很高的时候，或者当食物相对匮乏时(例如，在禁食或长时间运动期间)，有助于为机体调动能量底物。GCs通过增加肝脏葡萄糖产量和限制葡萄糖进入骨骼肌来增加血糖水平，这是没有争议的。大多数文献、期刊和网站还指出，GC有助于动员脂肪细胞中的游离脂肪酸(FFA)，通过增加脂肪组织脂肪酶的表达和/或活性，帮助为运动和应激反应中的能量代谢提供燃料。然而，我们和其他人最近开始发现，事实上，GC以剂量依赖的方式迅速降低脂肪细胞中的脂解率，并减少FFA的动员，至少在短期内是这样。这项计划更新的目的是确定应激(即运动、禁食、神经源性应激)期间GC增加的生理学相关性，以及GC在脂肪组织动员中起相反作用的潜在机制。我们假设，虽然GC可能通过改变关键限速脂肪酶的基因转录来改变脂解的“机制”，但它们实际上是通过快速的非基因组作用来抗脂的。这项提案中概述的实验将提供关于糖皮质激素如何在应激反应中改变脂肪组织代谢的新的和重要的信息。这项研究继续为对自然科学感兴趣的生理学和新陈代谢领域的学员提供一个出色的环境。

Glucocorticoids (GCs) are naturally produced steroid hormones released by the activation of the hypothalamo-pituitary-adrenal (HPA) axis in a circadian rhythm and during times of stress (such as with exercise or starvation). GCs such as cortisol (humans) or corticosterone (rodents) have long been thought to be critical in helping to mobilize energy substrates for the organism when energy demands may be high and perhaps when food is relatively scarce (i.e. during fasting or during prolonged exercise). It is without controversy that GCs increase blood glucose levels by increasing hepatic glucose production and by limiting glucose disposal into skeletal muscle. Most texts, journals and websites also state that GCs help mobilize free fatty acids (FFAs) from adipocytes to help provide fuel for energy metabolism during exercise and a stress response by increasing adipose tissue lipase expression and/or activity. However, we and others have recently begun to discover that GCs, in fact, rapidly lower lipolysis rates in a dose-dependent fashion in fat cells and reduce FFA mobilization, at least in the short term. The purpose of this program renewal is to determine the physiological relevance of increases in GCs during times of stress (i.e. exercise, fasting, neurogenic stress) and the underlying mechanisms by which GCs have opposing roles in adipose tissue mobilization. We hypothesize that while GCs may change the "machinery" for lipolysis by changing gene transcription of key rate limiting lipases, they are actually antilipolytic via rapid non-genomic actions. The experiments that are outlined in this proposal will provide novel and important information about how GCs alter adipose tissue metabolism during a stress response. This research continues to provide an outstanding environment for trainees in the field of physiology and metabolism who are interested in Natural Sciences.