In a recent paper published in Cell, Dr Agatha van der Klaauw and colleagues in Professor Sadaf Farooqi’s team describe the role of a group of neural guidance molecules, the Semaphorins in the development of hypothalamic brain circuits that regulate body weight.
The team characterised rare genetic variants affecting the function of multiple genes encoding the Semaphorin3 ligands, receptors and co-receptors in people with severe obesity recruited to the Genetics of Obesity Study (www.goos.org.uk). They showed that deletion of these genes in zebrafish caused increased growth and/or adiposity, that deletion of the Semaphorin receptor, Neuropilin-2, in the hypothalamus caused mis-wiring in the hypothalamus and weight gain in mice and that human variants reduced the ability of these molecules to guide neurons precisely to their destination in the hypothalamus. In this study, researchers show that genetic disruption of the connections between brain circuits in the hypothalamus can affect body weight. The team continues to study the role of neural guidance molecules in obesity and other hypothalamic diseases.