Molecular and pathophysiological mechanisms in human obesity

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.

While the modern ?obesogenic environment is clearly driving secular trends in the prevalence of obesity, inter-individual differences in susceptibility to such influences are largely genetically determined. With MRC Programme grant support since 1999 we have developed a comprehensive programme of research into molecular and pathophysiological factors in human obesity, discovering several monogenic causes of severe, early-onset human obesity, utilizing the detailed study of such individuals to gain novel insights into control mechanisms underlying energy balance and other phenotypes in humans, and targeting therapy to genotypically defined subgroups. We have, more recently contributed to global efforts in discerning the set of more common genetic variants which underpin variation in adiposity across populations and are deeply engaged in attempts to understand the biology linking such variants to adiposity.
In relation to severe early-onset obesity we propose i) To use targeted candidate gene analysis to discover and subsequently fully characterise novel, highly penetrant genetic causes of extreme early-onset obesity in three specific subphenotypes a) obesity with developmental delay b) obesity with neuroendocrine dysfunction c) obesity with disordered sleep/arousal ii) Having recently detected leptin receptor mutations in 2% of our GOOS cohort, to establish the contribution of such mutations to the obese phenotype and to exploit a series of naturally-occurring mutations to gain insights into structure/functional relationships within the leptin receptor iii) Having recently demonstrated a key role for the MC4R in the control of human blood pressure through the examination of MC4R haploinsufficient patients vs. matched equally obese controls to explore the longer term effects of MC4R deficiency on cardiovascular health.

In relation to the biology of common human obesity we propose i) To better understand the role of the gene (FTO) variants in which are most strongly associated with common human obesity, in the control of mammalian energy balance through studies in rodents and humans ii) To build on our recently reported discovery that FTO is a 2OG-dependent dioxygenase to understand the fundamental functions of FTO including its interactions with other proteins and its targets and how this relates to its physiological functions iii) To apply similar approaches to the understanding of the biology of other novel and highly validated obesity genes emerging from ongoing hypothesis-free approaches.

We will bring a comprehensive, multidisciplinary approach to these problems using studies in vitro, in cellular systems, in rodent models and in humans.