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Title: The effect of gut hormones on metabolism and energy homeostasis
Author: Hostomska, Klara
ISNI:       0000 0004 2713 4543
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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The increasing prevalence of obesity, and its associated morbidity and mortality, together with limited treatment options, underscores an urgent need for investigation into effective therapeutic interventions. Gut hormones have been identified as integral factors in the regulation of appetite. This thesis examines two signalling systems involved in the gastrointestinal regulation of energy homeostasis: Peptide YY (PYY) and Proglucagon-derived peptides. PYY is a gut hormone released from the L cells of the intestine after the ingestion of food and elicits its effects via the Y2 receptor. The predominant circulating form of PYY, PYY3-36, has been shown to acutely reduce food intake when administered peripherally at physiological concentrations in both lean and obese rodents and humans. However, several groups have shown that continuous administration of PYY3-36 via osmotic mini-pumps results in a transient reduction in food intake. It has been suggested that an apparent desensitisation to the anorectic effects of PYY3-36 may be due to the physiological defence of body weight and counter regulatory mechanisms; however tolerance due to receptor downregulation may also occur. In this thesis, I aimed to elucidate if the transient anorectic effect of PYY3-36 is a result of direct tolerance to the peptide itself or if this is indirect, due to the homeostatic defence of body weight. I have shown that the anorectic effect of PYY3-36 is attenuated following prior exposure to a low dose, suggesting tolerance at the receptor level. In addition, animals which were food restricted preceding an infusion of PYY3-36 remained sensitive to the anorectic effects, suggesting that body weight change alone cannot result in the hyperphagic response. However, no change in Y2 mRNA receptor expression following PYY3-36 infusion was detected. The proglucagon peptide family includes the hormones Glucagon like peptide-1 (GLP-1) and Glucagon (GCG). GLP-1 is release from the L-cells of the intestine in response to food intake and has known actions as a satiety factor and incretin hormone. GCG is released under fasting conditions and in response to adrenergic stimulation to stimulate gluconeogenesis and glycogenolysis, as well as to increase energy expenditure. Recent evidence suggests that simultaneous co-agonism of the GLP-1 and GCG receptors may be beneficial to the treatment of obesity and diabetes. In this thesis, I explore the development of a GLP-1R and GCGR co-agonist which reduces food intake and increases energy expenditure in rodents. Furthermore, to investigate the mechanism of GCG agonism on energy expenditure, I evaluate the effect of the specific dual agonist, GX6, on metabolic gene expression in brown adipose tissue and the liver. Overall, this thesis evaluates the potential roles of PYY, GLP-1 and GCG receptor agonism as novel therapies for obesity.
Supervisor: Murphy, Kevin ; Waljit, Dhillo ; Bloom, Steve Sponsor: Centre for Mammalian Physiology and Pharmacology
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral