Obesity represents an ever increasing global health burden. It results from the deregulation of energy intake and energy expenditure, ultimately causing a positive energy balance. Control over the coordinated regulation of energy balance is governed by highly specialised neurons in the central nervous system, specifically in the hypothalamus. Here, specialised neurons receive information about the energy state of the organism via hormones such as leptin and insulin. These neurons are characterised by the expression of certain messengers, i.e. neuropeptides, which in turn regulate food intake. In the hypothalamus two key neuron populations in this regulatory pathway comprise on the one hand neurons, which when activated promote food intake (orexigenic neurons), while on the other hand anorexigenic neurons suppress food intake upon activation. A major population of these anorexigenic, food intake supressing neurons is characterised by the expression of the neuropeptide proopiomelanocortin (POMC). Inactivation of POMC accordingly results in massive obesity in both mice and humans. Thus, these specialised cells are key to the integrated regulation of energy homeostasis. While only 3000-5000 of these cells exist in mice and humans, recent experiments have indicated that these cells are heterogenous. However, the specific function and consequences of this heterogeneity remain unaddressed. Therefore, the overarching aim of this project was to define the molecular basis and functional significance of this heterogeneity in these critical metabolism-regulatory neurons, with the ultimate perspective to develop novel pharmacological modulators to target these specific cell types as a novel approach for the treatment of obesity and diabetes mellitus.
