High-throughput in vivo profiling of candidate human obesity genes in zebrafish

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Maintaining a healthy body weight is key to reducing disease risk. Obesity - an increase in body weight to an unhealthy level - is strongly associated with a range of diseases including cardiovascular disease, diabetes and cancer. Further, obesity places a huge burden on healthcare systems. In the UK alone, treating obesity-related medical conditions costs the NHS ~£5 billion/year with wider societal costs estimated at ~£27 billion/year. Therefore, understanding mechanisms that cause obesity is of primary public health importance. Clinical sequencing studies, such as the Genetics of Obesity Study (GOOS; goos.org.uk) have identified hundreds of genes that are associated with severe obesity in both children and adults. It is now vital to understand which genes, when their functions are disrupted, cause obesity. Such knowledge will greatly improve our ability to therapeutically target molecules to prevent and ameliorate obesity. However, identifying which genes cause obesity, as opposed to being only associated with obesity, requires extensive functional experimentation in the laboratory. Moreover, current strategies to test how genes cause obesity are imperfect and rely on culture of cells in petri dishes, or expensive and time-laborious methods using rodents. In this proposal, we will use zebrafish - a small freshwater fish - to test whether genes cause obesity. The advantages of using zebrafish are that (i) gene function is tested in living animals, and therefore gene roles will be assessed within an endogenous, physiologically-relevant context, (ii) many genes can be tested in an inexpensive and rapid fashion, providing extensive information on candidate human obesity genes, and (iii) the function of each gene can be visualized non-invasively in live animals using high-resolution imaging techniques. In particular, this project will focus on how candidate human obesity genes influence the function of neurons within the brain to regulate appetite, feeding behaviour and susceptibility to obesity. Our initial results have identified that Semaphorin 3 signalling modifies the development of feeding neurons, with subsequent effects on obesity. Primary objectives of this proposal are to (i) understand how Semaphorin 3 signalling influences the real-time activity dynamics of feeding neurons, and (ii) to identify which genetic variants in components of the Semaphorin 3 signalling pathway influence obesity. Altogether, the results from this project will identify new candidate obesity genes in humans and provide novel information on how candidate obesity genes influence the real-time activity of feeding neurons. These results will help stimulate the development of novel anti-obesity therapies.