Central control of body weight and satiety regulation

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The development of obesity in industrial and low- and middle-income countries is leading to a severe burden for patients and health care systems based on associated comorbidities as cardiovascular diseases and type 2 diabetes mellitus. For this reason, it is of importance to understand the underlying molecular mechanism. Here, the identification of animal models and patients with rare monogenic forms of obesity has led to fundamental new insights into central regulation of body weight. So far, the majority of mutations are observed in genes embedded in the so-called leptin melanocortin signaling pathway and are leading to hyperphagia and early onset obesity. The hormone leptin, secreted in the adipose tissue, activates leptin receptors in the hypothalamus, which in turn activates POMC (pro-opiomelanocortin) expressing neurons and this is leading to the production of melanocyte stimulating hormone (alpha- and beta-MSH). Alpha- and beta-MSH are able to activate the melanocortin 4 receptor (MC4R) and induction of satiety. Obese patients with a mutation within this pathway exhibit frequently additional clinical features as e.g. impaired pubertal development. However, the complete phenotypic spectrum and functional impact of certain gene mutations remain unclear, though this would be essential to elucidate the overall functions of these genes. Apart from additional clinical aspects, hyperphagia and obesity are the main symptoms and unfortunately, conservative treatment options and in most cases even bariatric surgery are not successful to ensure reduction of body weight in these particular patients. For this reason, it is of importance to identify new treatment options. Recently, I have performed an investigator-initiated trial with a MC4R agonist, which led in POMC and LEPR deficient patients to sustained weight loss, illustrating this medical need for pharmacological treatment options. With this application, I want to elucidate the functional impact of gene mutations within the leptin melanocortin pathway using induced pluripotent stem cells (iPSC) from patients which are differentiated into hypothalamic neurons. Furthermore, this approach will be accompanied by a detailed clinical characterization of the patients to clarify the role of the affected genes in human physiology. Finally, the established stem cell based in vitro system allows the investigation of different compounds like leptin sensitizers, which might improve pharmacological treatment strategies of patients with these rare diseases. By this approach, I want to gain new fundamental insights into the central regulation of body weight based on the analysis of rare forms of obesity, which could lead to new therapeutic options and which could potentially be transferred to patients with more frequent genetic variants in common forms of obesity.