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Title: Engineering an oxyntomodulin analogue for weight reduction
Author: Price, Samantha
ISNI:       0000 0004 6495 5244
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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There is currently a lack of safe and effective treatments for obesity. The administration of long acting analogues of satiety gut hormones has been suggested as a potential weight loss pharmacotherapy. The gut hormone oxyntomodulin is a natural dual agonist that generates weight loss by reducing food intake and increasing energy expenditure; effects which are believed to be mediated by the GLP-1 receptor and glucagon receptor respectively. Previously designed long acting oxyntomodulin analogues have limited potency compared to native glucagon and GLP-1, due to the addition of large molecules to enhance circulatory half-life. Previous research in this lab has developed a slow release formulation that facilitates depot formation, allowing gradual peptide release over an extended period of time. The first half of this thesis details the development of a potent oxyntomodulin-like (OXL) dual agonist. A combination of conservative substitutions to the amino acid sequence of glucagon that improve in vitro GLP-1 receptor efficacy without diminishing glucagon receptor activity are identified. Addition of a histidine ‘tail’ enhances the in vivo pharmacokinetic profile of these OXL analogues, which is likely to be due to improved interaction with the slow release diluent. Feeding studies in mice and rats demonstrate significant food intake reduction and weight loss following acute and chronic analogue administration. Metabolic analysis demonstrates that the optimised analogue OXLT9 increases energy expenditure in rats. Reductions in fat mass and improvements in blood glucose homeostasis are observed following chronic administration of OXLT9 in DIO mice. The second half of this thesis investigates the increase in food intake following low doses of OXL analogues that was observed during analogue screening, and results suggest that this phenomenon is probably specific to rats. The novel effects of GLP-1 receptor selective Glu-3 OXL analogues on bodyweight are also investigated. Findings indicate they may act as antagonists at the human and rat glucagon receptors and could block endogenous glucagon activity; making them unsuitable tools to investigate the mechanisms of oxyntomodulin activity in rat models. The studies described in this thesis identify a potent dual agonist at the glucagon receptor and GLP-1 receptors that has the potential for once monthly administration as a weight loss therapy in man. Investigation of the novel food intake effects of low dose OXL analogues provides a starting point for further examination of analogue effects on energy expenditure and may be of relevance for human studies using oxyntomodulin-like analogues.
Supervisor: Bloom, Steve Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral