Modelling neurodevelopmental and molecular mechanisms of human genetic obesity

The principal goal of this proposal is to develop novel platforms to study neurodevelopmental and mechanistic causes of severe obesity. Body weight regulation is governed by the hypothalamus and this is established very early in human development. Genetic variants that disrupt hypothalamic function can lead to severe obesity. However, the manner in which these variants contribute to obesity by exerting neurodevelopmental and molecular changes have been difficult to study since human brain tissue is inaccessible. Rodent models have been used to improve our understanding of energy homeostasis, but they carry inherent limitations due to inter-species differences in brain structure and physiology, as well as gene sequences. 

The development of human study systems for disease modelling is an important complementary approach to animal and patient studies. We will use several novel methodologies – precise genome engineering with CRISPR/Cas9 in stem cells, 2D hypothalamic cultures, as well as 3D brain organoids – to generate physiologically relevant cellular and tissue models of human genetic obesity. We will investigate neurodevelopmental aspects of the disease and use the models to study molecular mechanisms that leads to obesity.