Investigation of the physiological role of hypothalamic glucocorticoids in the regulation of energy homeostasis

肥胖是英国的一个主要公共卫生问题。目前唯一真正有效的治疗方法是肠道旁路手术。这是非常昂贵的执行，只能用于最肥胖的人。一个更实际的方法是开发一种药物疗法。然而，大脑和周围的许多系统都参与了食欲和能量消耗的调节。因此，如果我们要开发一种成功的药物来治疗肥胖，我们需要了解这些生理系统。糖皮质激素是被认为参与食欲调节的激素。它们是由肾上腺产生的，作为应激反应的一部分发挥着重要作用。糖皮质激素通常作为一种治疗给予患者。它们的主要副作用之一是增加食欲和肥胖。然而，目前尚不清楚它们在日常食欲调节中是否重要，以及如果重要，则对食欲调节的影响在体内何处发生。我已经进行了初步实验，表明它们作用于大脑中称为下丘脑的部分，增加食物摄入量，减少能量消耗。该项目将确定糖皮质激素在控制食物摄入和能量消耗方面的重要性，并确定它们是否可能在肥胖症的发展中起重要作用。该项目是基于操纵一种在大脑中产生糖皮质激素的酶，称为11 β HSD1。目前，抑制这种酶的药物正在试验作为肥胖及其相关疾病的潜在治疗方法。然而，这些治疗并不是专门针对大脑中的11 β HSD1。专门针对大脑的药物可能更有效，并减少副作用。该项目的工作将为此提供证据，并可能导致开发更有效的治疗肥胖和相关疾病的疗法。

Obesity is a major public health problem for the UK. Currently the only truly effective treatment is gut bypass surgery. This is very expensive to perform and can only be used on the most obese people. A more practical approach would be to develop a drug therapy. However many systems in the brain and in the periphery are involved in the regulation of appetite and energy expenditure. Therefore if we are to develop a successful drug to treat obesity we need to understand these physiological systems. Glucocorticoids are hormones thought to be involved in the regulation of appetite. They are produced by the adrenal glands and have a major role as part of the stress response. Glucocorticoids are commonly given as a treatment to patients. One of their main side effects is increased appetite and obesity. However it is not currently known whether they are important in the day to day regulation of appetite and if so where in the body the effect on appetite regulation occurs. I have conducted pilot experiments which suggest that they act in a part of the brain called the hypothalamus and increase food intake and reduce energy expenditure. This project will establish the importance of glucocorticoids in controlling food intake and energy expenditure and determine if they may be important in the development of obesity. The project is based on manipulating an enzyme which produces glucocorticoids called 11betaHSD1 in the brain. Currently drugs which inhibit this enzyme are being trialled as potential treatments for obesity and its related disorders. However these treatments are not designed specifically to target11betaHSD1 in the brain. It is possible that drugs which specifically target the brain may be more effective and reduce side effects. The work in this project will provide the evidence for this and may lead to development of more effective therapies for treating obesity and related conditions.