Molecular pharmacology of beta adrenoreceptors in multiple disease states

对于近一半的成年人来说，肥胖是一个日益严重的主要健康问题，并与糖尿病和心脏病等严重疾病有关。行为上的改变，如增加体育活动和少吃高热量食物，帮助许多人减轻了体重，然而，还有许多人有超重的遗传倾向，行为措施是无效的。虽然抗肥胖药物应该是改变生活方式的一种有价值的辅助手段，但目前可用的食欲抑制剂并不理想。我们的工作包括研究特定的细胞表面蛋白质（受体），这些蛋白质通常对肾上腺素等激素有反应。已知β(3)-肾上腺素能受体介导脂肪的分解和脂肪组织（可能包括肌肉）中热量产生的增加。给肥胖小鼠服用β(3)选择性药物可以促进体重减轻和减轻糖尿病症状，制药公司正在开发一些针对人类β(3)-肾上腺素能受体的药物。我们正试图更多地了解这种受体的特性，因为这些信息将有助于设计更具选择性和更有效的药物。有时药物作用于不止一种受体，有证据表明，CGP 12177和BRL 37344两种药物可能就是这种情况，它们刺激β(3)-肾上腺素能受体。我们项目的第二个主要目标是找出这些药物是否作用于一种新的受体，这种受体与β(3)-肾上腺素能受体有关，并介导脂肪组织和骨骼肌的能量消耗和热量产生。新受体的发现将为开发有效的抗肥胖疗法提供额外的空间。

Obesity is a major and increasing health concern for almost half the adult population, and is associated with serious medical conditions including diabetes and heart disease. Changes in behaviour such as increasing physical activity and eating less high-calorie food help many people reduce their body weight, however many others have a genetic predisposition to become overweight and behavioural measures are ineffective. Although anti-obesity drugs should be a valuable adjunct to lifestyle changes, the currently available appetite suppressants are not ideal. Our work involves studying particular cell-surface proteins (receptors) which normally respond to hormones such as adrenaline. The beta(3)-adrenergic receptor is known to mediate the breakdown of fats and increased heat production in adipose tissue and possibly muscle. Administration of beta(3)-selective drugs to obese mice promotes weight loss and a reduction of diabetic symptoms, and a number of drugs targetting the human beta(3)-adrenergic receptor are being developed by pharmaceutical companies. We are trying to understand more about the properties of this receptor, as this information will assist in designing drugs which are more selective and more potent. Sometimes drugs act at more than one receptor, and there is evidence that this may be the case for two drugs called CGP 12177 and BRL 37344 which stimulate the beta(3)-adrenergic receptor. The second major aim of our project is to find out whether these drugs act at a novel receptor which is related to the beta(3)-adrenergic receptor and also mediates energy expenditure and heat production in adipose tissue and skeletal muscle. The discovery of a new receptor would provide additional scope for the development of effective anti-obesity treatments.