Genetic approaches in the GOOS cohort are leading to the discovery of new obesity genes whose function we study using a number of molecular and cellular approaches depending on the nature of the molecule that is disrupted. These molecular studies play a critical role in laying the foundation for the development and validation of new drug targets for obesity.
For example, we have identified a gene called Kinase Suppressor of Ras 2 (KSR2). KSR2 is involved in coordinating intracellular signals via the ERK and AMPK signalling pathways, which are responsible for cell growth and energy utilization, respectively. Mutations in KSR2 can disrupt signalling through these pathways leading to hyperphagia, insulin resistance and reduced basal metabolic rate in individuals. In fact, mutations in KSR2 are the first to be discovered that decrease the basal metabolic rate in some people. In a cell model, treatment with the often-prescribed anti-diabetic drug metformin rescues the defects in fatty acid oxidation seen in cells, suggesting a possible treatment for individuals with KSR2 mutations.
We use a range of state-of-the-art cell biology/molecular biology techniques (including CRISPR/Cas) and are setting up high throughput techniques to study the functional effects of mutations at the protein and cellular level. We are currently looking at mutations in G-protein coupled receptors, transcription factors and signalling molecules, several of which are potential drug targets for obesity and metabolic disease. Through our on-going cutting edge research we continue to identify new mutations linked with obesity, and determine the consequences these mutations have on individuals.
During his time at Harvard University, Florian developed methods to generate hypothalamic neurons from human stem cells, including those that regulate feeding behaviour such as POMC neurons and AGRP/NPY neurons. This is an important step forward for obesity research, since many of the genes implicated in obesity are expressed in neurons in the hypothalamus, particularly those that regulate feeding behaviour. The Merkle laboratory will use human hypothalamic neurons to study the molecular and cellular basis of obesity with the aim of developing better therapies. In particular, mutations identified in obese people can be introduced into human stem cells by gene editing with the CRISPR/Cas9 system. Neurons derived from these cells can then be studied to test whether the mutations affect how the neurons send electrical impulses, which genes they express and how many synapses they make, all processes that could contribute to obesity. These neurons could also be used to screen for novel therapeutic agents and to test the responses of neurons to existing therapies.