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产生了影响。肥胖增加了许多疾病的风险，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，也会损害个人的工作能力。这个问题的核心是能量平衡，也就是从食物中摄入的能量和身体消耗的能量之间的差异。虽然一个明显的解决方案是减少高热量食物的摄入，增加个人的锻炼，但在这方面的国家战略未能阻止肥胖的增长（或实际上减缓增长的速度）。此外，一旦一个人肥胖，他可能很难锻炼和减少肥胖。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（如胰岛素抵抗、冠状动脉疾病）的许多危险因素。几种类型的药物靶向脂肪细胞中发现的两种蛋白质，ppar - γ和ppar - δ。这些蛋白质反过来“开启”对脂肪代谢或脂肪储存很重要的基因。虽然对PPAR-gamma（治疗II型糖尿病的已知靶点）进行了大量的研究，但对PPAR-delta的研究相对较少。本研究结合动物实验和体外细胞培养，探讨了这两种受体在脂肪细胞能量平衡中的作用。为此，我们将研究两种靶向小鼠脂肪组织中ppar - γ或ppar - δ的药物的作用，并利用质谱和核磁共振（NMR）光谱研究它们如何改变关键代谢物的浓度，利用DNA微阵列研究基因表达，利用基于质谱的蛋白质组学研究蛋白质含量。然后，收集到的数据将通过统计学进行数学建模，以产生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，从而探索作用机制。这项工作将增加我们对脂肪细胞中控制能量平衡机制的认识，也使我们能够开发一种实验方法，可用于了解其他生化过程。此外，获得的信息将有助于更好地描述肥胖和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.