Molecular and pathophysiological mechanisms in human obesity

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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.