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Title: G-protein signalling pathways and appetite regulation
Author: Gibson, W. T.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2005
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The objective of the work presented here was to screen genes involved in appetite regulation, with a focus on orexigenic signalling. The following genes were screened: the serotonin receptor 5HT2c, the melanin-concentrating hormone receptors types 1 and 2 (MCHR1 and MCHR2) and the gene for the orexigenic ligand agouti-related peptide (AGRP). Several previously-unknown DNA variants were detected. Of greatest interest were mutations that changed coding amino acids. A Thr419Ala variant in 5HT2c cosegregated with obesity over two generations in a British Caucasian family, and was not detected among 192 controls. Nonconservative variants found in MCHR1 were Tyr181His and Arg248Gln. The latter cosegregated with obesity in the proband’s nuclear family, and neither MCHR1 coding variant was detected in 262 controls. Functional testing of the mutant receptors was done in collaboration with other investigators. No differnces between the signalling properties of the wild type and mutant 5HT2c proteins were found. Constitutive activity of the MCHR1 variant proteins could not be demonstrated with certainty. Population studies among British Caucasians found no association between common MCHR1 variants and obesity phenotypes. However, association studies using the c.123G>A and c.199G>A variants in AGRP revealed and association between body-mass index, total fat mass and the rare alleles. This association was highly significant (p<0.0001), and specific to females. Several novel variants in genes involved in appetite regulation are presented here. Functional consequences for the rare nonconservative variants have yet to be verified. However, a potentially intriguing association exists between common SNPs in the AGRP gene and fat accumulation in women.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available