Deciphering the Melanocortin System: Three Distinct Approaches

Human obesity is a multi-factorial trait regulated by environmental and genetic factors and is considered to be a global epidemic associated with mortality. Therefore, understanding the molecular pathways controlling the energy homeostasis is of great importance in order to develop pharmaceutical agents to treat obesity. This thesis work includes four separate research projects with the common intention of exploring the central control of energy homeostasis using three distinct research approaches. Leptin-melanocortin axis is the major central regulator of energy homeostasis where MC4R and POMC play key roles in transmitting the anorexigenic signal of the adipocyte secreted hormone leptin. In a genetic linkage study, we demonstrated that naturally occurring MC4R mutations but not the POMC or MC3R mutations are strongly associated with human obesity. Secondly, in an attempt to determine an alternative signaling pathway to leptin, the inhibition of Gi protein signaling in the POMC neurons decreased the energy expenditure in a transgenic mouse model. Finally, we scrutinized the molecular mechanism underlying the physiologically relevant constitutive activity of MC4R. The data supports the evolutionary role of the N-terminal domain in the activity regulation of the G protein-coupled receptors. Overall, our findings provide essential pieces to the bigger puzzle of the melanocortin system, and contribute to the biomedical research in the pursuit of understanding the regulation of energy homeostasis in humans