Determinin the CNS action of anorectic gut hormones in humans using functional MRI

Abstract

Understanding how the brain controls appetite offers promising inroads towards developing new therapies for obesity. Peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) are anorectic hormones that are co-released post-prandially by the gut. Both have been shown to physiologically inhibit appetite and food intake when administered to humans. However, the mechanisms by which they regulate appetite through the central nervous system (CNS) remain poorly understood. Functional magnetic resonance imaging (fMRI) is a tool that has recently been used to determine the CNS pathways that mediate the action of appetite-modulating hormones. This dissertation investigates the action of the anorectic gut hormones PYY3-36 and GLP-17-36 amide, infused intravenously over 90 minutes in 15 lean, healthy human subjects following an overnight fast. Using blood oxygen level dependent (BOLD) fMRI, I have determined the effects of PYY3-36 and GLP-17-36 amide on CNS appetite centres and subsequent food intake, comparing the effects with those seen physiologically following a standard meal. The combined administration of PYY3-36 and GLP-17-36 amide to fasted human subjects led to similar reductions in BOLD fMRI brain activity in a priori regions of interest as observed physiologically following feeding, especially in the insular cortex. Additionally, compared with infusion of saline, co-administration of PYY3-36 at 0.3 pmol/kg/min with GLP-17-36 amide at 0.8 pmol/kg/min led to a 27.0% reduction in ad libitum energy intake at a buffet lunch served immediately after the infusion. The reduction in ad libitum energy intake following the combination infusion of PYY3-36 and GLP-17-36 amide was similar to that observed when saline was infused in subjects following consumption of a set breakfast (23.5% reduction in ad libitum energy intake at a buffet lunch served immediately after the infusion). My findings provide direct evidence that the combined action of PYY3-36 and GLP-17-36 amide in the brain could explain post-prandial satiety.