Molecular and pathophysiological mechanisms in human obesity

肥胖是一个重要的医学问题，因为它会导致糖尿病、心脏病发作和中风的过早死亡，也会导致相当多的慢性疾病和生活质量下降。虽然很明显，最近大多数人群肥胖频率增加的原因必须在于食物的可用性，成本和质量以及体力活动需求减少等因素的变化，但同样重要的是要问为什么面对这些环境因素，有些人保持苗条，而另一些人则增加体重。我们从对双胞胎和收养儿童的研究中得知，遗传是决定肥胖风险的一个非常重要的因素。事实上，在一些儿童非常严重的肥胖，从一个年轻的年龄，我们已经发现突变的单基因是足以在自己的结果在孩子？s肥胖。在一种情况下，我们已经能够完全治愈肥胖取代？坏了？基因产物我们研究了一组约3500名严重肥胖的儿童，到目前为止，我们发现其中约10%的儿童存在导致肥胖的单一基因突变。寻找疾病基因的新技术现在已经出现，我们希望使用一系列新的方法来试图找到这些儿童肥胖的原因。我们希望通过了解原因，我们将能够更好地进行针对性治疗。除了导致儿童病态肥胖的严重突变外，最近还发现了其他微妙的遗传变异，每一种都很常见，并改变了一个人？He’他的体重减轻了几磅。这些变异中的一些基因预计不会对体重产生影响。我们还计划更好地了解这些基因是如何影响体重的，以及通过药物、饮食或运动来操纵它们是否可能为治疗肥胖提供新的方法。

Obesity is an important medical problem as it can lead to early death from diabetes, heart attacks and strokes and also causes considerable chronic ill health and a lowered quality of life. While it is clear that the reasons behind the recent increase in the frequency of obesity in most populations must lie in changes in factors such as the availability, cost and quality of food and the reduction in the need for physical activity it is also important to ask why, in the face of these environmental factors some people stay slim while others gain weight. We know from studies of twins and adopted children that genetics is a very important factor in determining the risk of becoming obese. Indeed in some children with very severe obesity from a young age we have found mutations in single genes that are sufficient in themselves to result in the child?s obesity. In one case we have been able to completely cure obesity by replacing the ?broken? gene product. We study a group of ~3500 severely obese children and so far have found a single gene mutation causing obesity in about 10% of these. New techniques for finding disease genes are now available and we want to use a range of novel approaches to try to find the causes of obesity in the rest of these children. We hope that by knowing the cause we will be able to better target treatment. As well as the severe mutations that result in morbid obesity in children there are other more recently discovered subtle genetic variants each of which are common and alter a person?s weight by a few pounds. Some of these variants are in genes that were not expected to have an effect on body weight. We also plan to better understand how those genes contribute to body weight and whether manipulating them by drugs, diet or exercise might provide new approaches to treating obesity.