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Title: Development of obestatin analogues and investigation of their effects on metabolism in obesity and type 2 diabetes
Author: Cowan, Elaine
ISNI:       0000 0004 6056 8140
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2016
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Obestatin is a 23 residue gastrointestinal peptide with alpha-helical structure, short half-life, and as yet, no identified receptor. Since discovery in 2005, it has been reported to have many beneficial metabolic and cardiovascular actions in normal physiology and experimental obesity/diabetes, a number of which have been confirmed and disputed. This thesis aimed to characterise the structure and activity of obestatin (1-23) and obestatin analogues in vitro, and to undertake in vivo studies to examine their metabolic actions and biochemical pathways. Initially, N-PEGylated obestatin (PEG-OB(1-23)) was chronically assessed and found to have no significant effects in standard diet fed rats of normal physiology and in high fat diet fed (HFF) rats of mild obesity without metabolic dysfunction. Subsequent in vitro investigations with three novel N-PEGylated analogues incorporated with disulphide bridges, PEG-OB(1-23) and native obestatin showed that whilst none of these could activate putative receptors, novel analogue PEG-OB(Cys10,Cys13) with less alpha-helicity had the most promising stability (>4 times) and activity profile (effects slightly improved or comparable in pancreatic beta-cells, isolated mouse aorta and endothelial cells) compared to native obestatin. This analogue was assessed chronically in a more severe animal model of obesity/diabetes and found to inhibit cumulative weight gain, improve glucose tolerance and reduce diet induced increases in pancreas and white adipose tissue (WAT) weights, terminal insulin, c-peptide 2, HOMA-IR and HOMA-B levels in diet induced obesity (DIO) mice. Furthermore it induced decreasing trends in pancreatic morphology parameters in lean and DIO mice, reduced surface body temperature in lean animals, and (via metabolomics analysis of terminal plasma) demonstrated obestatin involvement in phospholipid turnover, lipid homeostasis, insulin sensitivity, inflammation, steroid, bile acid, PAF and glutathione metabolism. Interestingly concurrent investigations also demonstrated improvements in animal vascular function and we propose that obestatin enhances nutrient disposal and insulin sensitivity at least partially via its vascular actions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available