| Summary: | Substantial evidence from rodent and human genetic models has identified the hypothalamic melanocortin system as a fundamental component of the neural network regulating energy homeostasis. The aims of this thesis were a) to examine the relevance of four components related to this pathway; proopiomelanocortin (POMC), cocaine and amphetamine-regulated transcript (CART) and corticotrophin-releasing factor receptors-1 and 2 (CRF-R1 and -R2), to severe human obesity through genetic studies, and b) to investigate the physiological roles of POMC and its derived peptides in the control of energy balance by gene targeting experiments in mice. Genetic analysis of <i>CART, CRF-R1 </i>and <i>CRF-R2</i> found that genetic variations within these <i>loci</i> were unlikely to significantly contribute to severe human obesity. In contrast, a mutation in <i>POMC</i> was found to confer susceptibility to early-onset human obesity through production of an aberrant peptide that was capable of acting as a competitive partial antagonist at an endogenous melanocortin receptor. In addition to confirming the importance of POMC in energy balance, the generation of <i>POMC-</i>deficient mice revealed novel physiological roles for POMC-derived peptides. Utilising a tau-lacZ neuronal reporter marker under the control of the endogenous POMC locus, it was demonstrated that POMC-expressing neurons are widely distributed throughout the brain. Finally, to elucidate the functions of specific POMC-derived peptides, a genetic strategy was designed to selectively inactivate POMC peptides in mice. These insights into components of the melanocortin signalling pathway may provide future therapeutic opportunities for the treatment of human obesity.
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