Burning fat: an in vivo and in vitro study of the role of PPAR-delta in regulating fat metabolism in adipose tissue

英国人越来越胖，这对国家的健康和财富都有影响。肥胖会增加患多种疾病的风险，包括2型糖尿病、心脏病、中风和高血压。这些疾病将给国民保健服务带来越来越大的负担，并损害个人的工作能力。这个问题的核心是能量平衡，基本上是作为食物进入的能量和身体的能量消耗之间的差异。虽然一个明显的解决办法是减少高热量食物的摄入量，增加个人的锻炼，但这方面的国家战略未能阻止肥胖的增加（或实际上减缓增长速度）。此外，一旦个体肥胖，则该人可能难以锻炼和减少肥胖。有迹象表明，增加身体能量消耗的药物可用于减少肥胖和与肥胖相关的其他疾病（例如胰岛素抵抗、冠状动脉疾病）的许多风险因素。几种类型的药物靶向脂肪细胞中发现的两种蛋白质，称为PPAR-gamma和PPAR-delta。这些蛋白质反过来“打开”脂肪代谢或脂肪储存中重要的基因。虽然已经进行了大量的工作来表征用于治疗II型糖尿病的已知靶点PPAR-gamma，但是对PPAR-delta进行的工作相对较少。该提案旨在研究这两种受体在脂肪细胞能量平衡中的作用，使用动物研究和体外细胞培养的组合。为此，我们将研究两种靶向小鼠脂肪组织中PPAR-gamma或PPAR-delta的药物的作用，并研究它们如何使用质谱和核磁共振（NMR）光谱改变关键代谢物的浓度，使用DNA微阵列的基因表达和基于质谱的蛋白质组学的蛋白质含量。然后，将通过统计学对收集的数据进行数学建模，以生成可以在基于细胞培养的实验中进行的假设。后一种方法使我们能够更容易地操纵系统，从而探测作用机制。这项工作将增加我们对脂肪细胞能量平衡控制机制的了解，并使我们能够开发一种可用于理解其他生化过程的实验方法。此外，所获得的信息将有助于更好地确定肥胖及其相关并发症的主要潜在药物靶点。

People in the UK are getting fatter and this has consequences for both the health and wealth of the nation. Obesity increases the risk of a number of diseases including type 2 diabetes, heart disease, stroke and high blood pressure. These diseases will place an increasing burden on the National Health Service and also impair the ability of individuals to work. Central to this problem is energy balance which put basically is the difference between energy coming in as food and energy expenditure of the body. While one obvious solution is to reduce intake of high calorie foods and increase exercise in individuals, national strategies in this area have failed to halt the increase in obesity (or indeed slow the rate of increase). Furthermore, once an individual is obese it may be difficult for that person to exercise and reduce obesity. There are indications that drugs that increase the energy expenditure of the body may be used to reduce obesity and many of the risk factors for other diseases associated with obesity (e.g. insulin resistance, coronary artery disease). Several types of drugs target two proteins found in fat cells referred to as PPAR-gamma and PPAR-delta. These proteins in turn 'switch-on' genes important in either fat metabolism or fat storage. While a large amount of work has been carried out characterising PPAR-gamma, a known target for treating type II diabetes, relatively little work has been performed on PPAR-delta. This proposal sets out to investigate the role that these two receptors play in energy balance in fat cells using a combination of animal studies and in vitro cell culture. For this we will investigate the action of two drugs that target either PPAR-gamma or PPAR-delta in adipose tissue in mice and investigate how they alter the concentration of key metabolites using mass spectrometry and Nuclear Magnetic Resonance (NMR) spectroscopy, gene expression using DNA microarrays and protein content by mass spectrometry based proteomics. The data collected will then be modelled mathematically by statistics to generate hypotheses which can be pursued in cell culture based experiments. The latter approach allows us to manipulate the system more easily and hence probe mechanisms of action. This work will increase our knowledge of the mechanisms controlling energy balance in fat cells and also allow us to develop an experimental approach which could be used to understand other biochemical processes. In addition the information obtained will help better characterise a major potential drug target for obesity and associated complications.