Investigation of gut hormone physiology in the regulation of appetite

Abstract

Peptide tyrosine tyrosine (PYY) and glucagon like peptide-1 (GLP-1) are endogenous, anorectic gut hormones released from entero-endocrine L cells. The aims of this thesis were to: investigate the breakdown of PYY using peptide analogues in vitro and in vivo, determine the stimuli for release of PYY and GLP-1 from L cells in vitro and finally to attempt to stimulate the endogenous secretion of PYY and GLP-1 and so suppress appetite in man. The breakdown of PYY was studied using specially designed PYY analogues with changes to known enzyme cleavage sites. Degradation of the analogues was studied by incubation with proteolytic enzymes. Receptor binding assays were carried out to confirm that changes to the PYY structure had not altered binding to the endogenous PYY receptors. In vivo studies in rodents previously confirmed an extended pharmacological profile of these analogues. In order to study the various stimulants for PYY and GLP-1 release, a primary L cell model was developed. This was used to study the effect of various nutrients: glucose, amino acids and short chain fatty acids (SCFA) on PYY and GLP-1 release. In mouse and human primary L cell cultures the SCFA propionate increased PYY release significantly compared to basal levels, indicating that propionate is a potent stimulus of PYY release. To further investigate the results of the in vitro work, a randomised, double blind, crossover study was carried out in human volunteers to evaluate the effect of propionate on appetite. Administration of propionate ester over six days reduced energy intake at a buffet meal by 18.8% compared to control (P < 0.05, n = 20). However, there was no significant change in plasma GLP-1 or PYY levels between the groups, possibly suggesting an alternative explanation for the reduction in appetite seen. This may provide an interesting avenue for future studies. These studies of the physiological mechanisms underlying release and degradation of PYY and GLP-1 may contribute towards the development of an anti-obesity therapy based around L cell stimulation.