Anorectic Gut Hormones PYY and GLP-1 on Brain Appetite Pathways: A Human fMRI Study.

Abstract

This thesis explores the roles of the gut hormones Peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) in the modulation of human brain reward pathways utilising functional magnetic resonance imaging (fMRI). PYY and GLP-1 are co-released post-prandially and both have been shown to reduce appetite and inhibit food intake when administered to humans. They have the potential to be developed into anti-obesity therapies, with the expectation that low-dose combination therapy may provide more effective weight loss and limited side effects. There are currently no safe and effective medications available to treat obesity, and yet this global health crisis continues unabated. In this context, a study of the mechanisms by which gut hormones exert their anorectic effects, may guide the rational development of new drugs. To date, the effects of GLP-1 alone and the ways in which PYY and GLP-1 combine to modulate brain activity in humans are unknown. This thesis contains a set of functional MRI experiments designed to determine these effects in healthy, fasted, normal-weight human subjects. Results are compared with the changes in brain activation patterns observed physiologically following a meal. For the first time in humans, I have demonstrated that, in conjunction with a comparable effect on lunchtime energy intake, combined infusion of PYY3-36 and GLP-17-36amide to fasted subjects results in a similar modulation of brain activity as observed following a large breakfast. This supports the proposal that these hormones are major physiological mediators of satiety in humans. Both the fed state and the administration of anorectic gut hormones to fasted subjects, reduces activation in multiple brain reward regions in response to visual food-cues. This confirms that circulating gut hormones modulate the hedonic processing of food. The lack of any obvious differential activation pattern between PYY3-36 and GLP-17- 36amide raises the possibility that they act at corticolimbic structures via a final common pathway.