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Title: The preproglucagon derived peptides and energy homeostasis
Author: Parker, Jennifer
ISNI:       0000 0004 2735 4714
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Obesity is a major contributor to the development of chronic diseases, and there is a paucity of effective treatments. Recent studies suggest that co-agonists at the glucagon-like peptide-1 (GLP-1) and glucagon receptor efficaciously reduce body weight and improve glucose homeostasis. This thesis explores the effects of glucagon, GLP-1 and the endogenous GLP-1/glucagon receptor co-agonist oxyntomodulin, on appetite and glucose homeostasis and their mechanisms. As expected, peripheral injection of GLP-1 or glucagon to fasted mice transiently reduced food intake. Interestingly, subanorectic doses of GLP-1 and glucagon potently inhibited food intake when combined. Agonists at the GLP-1 (GLPAg) and glucagon (GCGAg) receptors designed in this laboratory were found to have receptor affinities comparable with those of GLP-1 and GCG, but with a prolonged duration of action. When administered chronically, individually and in combination, to an obese mouse model, the combination of these peptides appeared to cause superior reduction in body weight and improvement in glucose tolerance compared to the individual peptides. The receptors and central appetite regulating centres involved in the response to anorectic doses of GLP-1, glucagon and oxyntomodulin were investigated. The pattern of c-fos immunoreactivity in response to glucagon was examined for the first time and appeared indistinguishable from that induced by GLP-1. Oxyntomodulin appeared to induce greater c-fos activation in the nucleus tractus solitarius (NTS) than either glucagon or GLP-1 at equivalently anorectic doses. No difference in the activation of catecholaminergic, preproglucagon or POMC expressing neurons in the NTS was seen between the three peptides. The anorectic effects of both oxyntomodulin and glucagon appeared to depend on the presence of the GLP-1 receptor. The effects of both glucagon and oxyntomodulin on blood glucose and insulin release in mice were investigated and found to be highly dose dependant. Surprisingly, high doses of glucagon did not have a detectable hyperglycemic effect and some evidence suggested this may be due to cross reactivity with the GLP-1 receptor. The GLP-1 receptor antagonist EX 9-39 had an unexpected hyperglycemic effect, present in GLP-1 receptor knockout mice suggesting an alternative mechanism of action. Overall the work contained in this thesis has added mechanistic information to our knowledge about the anorectic and glucoregulatory effects of the preproglucagon derived peptides and supports development of synthetic agonists of the glucagon and GLP-1 receptors as treatments for obesity.
Supervisor: Field, Benjamin ; Bloom, Steve ; Gardiner, James Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral