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Title: Molecular mechanisms involved in human obesity : insights from genetics
Author: Hung, C.-C.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2005
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The leptin-melanocortin system has been shown to be an important mechanism to relay peripheral signals of body energy store to the hypothalamic neural network to regulate energy homeostasis in rodents and humans. The aim of this thesis is to explore other potential components/mechanisms which might also contribute to the regulation of energy homeostasis. The genes which are studied in this thesis included single-minded 1 (SIM1) and tropomyosin-related kinase B (TrkB) which are implicated in the development of hypothalamus, PYY and NPY Y2 receptor (Y2R) which are putative components of the gut-hypothalamus pathway, and small heterodimer partner (SHP) which might contribute to adipogenesis. Genetic studies of the TrkB gene revealed several rare, novel mutations. The Y722C mutation resulted in impairment of the TrkB function and TrkB-mediated cellular responses to the neurotrophin. The de novo Y722C was associated with hyperphagia, severe obesity and complex neurological phenotypes, suggesting the role of TrkB in control of human appetite in addition to neurological development. Analysis of SIM1, PYY, Y2R and SHP found that genetic variations within these loci were unlikely to significantly contribute to sever human obesity. On the other hand, association studies on the common polymorphisms in these genes suggested contribution to birthweight, and obesity related phenotypes at the population level. These studies provide insights into the roles of these molecules in the regulation of energy homeostasis in humans.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available