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

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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.