Molecular characterization in human neurons of genes associated with severe obesity identified from consanguineous pedigrees.

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Obesity is a growing public health problem. While it has undoubtedly been driven by the changing environment, there is a large heritable component underlying the variation in body-weight within the population. Genetic studies point to the brain, in particular a region called the hypothalamus, as having a crucial role in modulating appetite. For example, mutations of single genes in the hypothalamic leptin melanocortin pathway leads to severe, early-onset obesity. Around 10% of severe human obesity currently has a clear identified cause, with the majority of mutations sitting within the genes encoding the melanocortin pathway. Thus, much of the genetic aetiology of severe obesity remains to be uncovered, identification of which could reveal novel pathways and potential therapeutic targets. However, studying the disease in inbred populations increases the chances of finding disease causing mutations. Using this approach, we have identified mutations in two new genes, ADCY3 and ROCK1, that are associated with severe obesity. In this proposal, we will study both these genes in detail. Given the role of the brain in the regulation of body-weight and food intake, we will characterize these genes in human neurons. We need to understand not only the function of these genes in normal cells but also the consequences of loss of function for the neuronal populations in which they are expressed. Although murine models have been hugely helpful in the past to overcome the difficulties of inaccessibility of the human hypothalamus, we believe studying human tissue from the relevant regions is essential to get a fuller understanding of the role of these genes. An existing collaboration with the Cambridge Brain Bank, allows us access to fresh and fixed human donor brain samples. The access to this precious material, coupled with recent developments in single cell sequencing and mapping technologies provides us with a timely opportunity to study where these genes are expressed in the human hypothalamus. Additionally, we have recently acquired the ability to generate, genetically manipulate and differentiate human stem-cells into hypothalamic neurons. This will allow us to directly examine the impact of these obesity associated mutations in the context of a relevant human cell. Using high-throughput DNA sequencing approaches, we will also continue our search for other new obesity candidates. Our current proposal is a collaborative venture between two UK centres of excellence in the study of the genetics of obesity. The group of Froguel, from Imperial College London, brings a large collection of severely obese children from highly consanguineous Pakistani pedigrees; and the group of Coll, O'Rahilly and Yeo, from the MRC Metabolic Diseases Unit at the University of Cambridge, who bring bespoke functional expertise and access to human hypothalamic samples. Our aim is to uncover novel appetite control pathways and reveal new potential therapeutic targets in order to tackle obesity.