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Title: Characterisation of oxyntomodulin and development of an oxyntomodulin analogue for use in metabolic research studies
Author: Minnion, James Stephen
ISNI:       0000 0004 2737 6489
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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This thesis characterises the gut hormone oxyntomodulin, and explores the role of the hormone in the regulation of food intake, energy expenditure and body weight. Oxyntomodulin is a 37 amino acid enteroglucagon peptide which is secreted from the endocrine cells of the small intestine in proportion to nutrient ingestion levels. Acute administration of oxyntomodulin has been shown to reduce food intake in rodents and humans. In addition, repeated infusion of oxyntomodulin resulted in reduction in body weight and adipose tissue in both rodents and humans. It is thought that many of oxyntomodulin actions are mediated via the glucagon-like peptide-1 (GLP-1) receptor. However, the glucagon (GCG) receptor or an unknown receptor may be partly responsible for mediating its actions. Oxyntomodulin is rapidly degraded by proteases, resulting in the peptide having a half-life of twelve minutes in man. I have characterised oxyntomodulin, measuring its binding affinity for and bioactivity at the GLP-1 and GCG receptor, its effect on acute food intake in rodents and ability to stimulate insulin release. To investigate the short half-life of oxyntomodulin I investigated its susceptibility to degradation by proteases known to be important in the regulation of related peptides. I demonstrated that oxyntomodulin is a weak insulinotropic agent and is a substrate for the proteases dipeptidyl peptidase-IV (DPP IV) and neprilysin. Oxyntomodulin is rapidly degraded by proteases, making investigation of its putative actions on energy expenditure difficult. To overcome this problem I used peptide analogues of oxyntomodulin to further investigate the structure function relationship of the molecule. Using information gained about its structure and functions, I designed an analogue of oxyntomodulin (6421) with an increased potency and longevity of food intake inhibition. The effect of chronic administration of 6421 on body weight changes and food intake was investigated in rodents and its effect on energy expenditure measured. I demonstrated that administration of the oxyntomodulin analogue 6421 caused a decreases in food intake and an increase in basal metabolic in rat. These two actions may be mediated by stimulation of the thyroid axis at the level of the hypothalamus and pituitary and/or by an increase in a-melanocortin stimulating hormone release in the hypothalamus.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available