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Title: The regulation of appetite by gut hormones
Author: Spreckley, Eleanor
ISNI:       0000 0004 6495 6212
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Food intake is essential to life, and thus the drive to eat is a priority. Hunger and satiety are governed by homeostatic and hedonic pathways. The homeostatic control of food intake is primarily mediated by nuclei of the hypothalamus and brainstem, while non-homeostatic control is predominantly afforded by the mesocortical and mesolimbic pathways. Hedonic drive to eat may override homeostatic control, leading to increased food intake. The increasing intake of calorie-dense, highly palatable food has contributed to escalating levels of obesity, which now represents a major public health burden. Thus, the development of appetite-reducing agents to combat the obesity epidemic is a priority. Non-specific appetite inhibitors often result in side-effects such as alterations in blood pressure, locomotor activity and disrupted eating patterns. If an appetite-reducing agent is observed to be acting specifically, it may represent a better target for the development of anti-obesity drugs. The anorectic gut hormones, peptide YY (PYY) and glucagon-like-peptide-1 (GLP-1), reduce food intake by peripheral mechanisms, and also have effects on central homeostatic and hedonic pathways. However, exogenous administration of these peptides results in nausea in humans and aversion in rodents at higher doses. This project investigated the effects of peripheral administration of GLP-1 and PYY on food intake, cardiovascular parameters and behaviour in rats. Feeding studies in fasted animals identified 1.5 nmol/kg as the minimally effective anorectic dose of PYY, while conditioned taste aversion (CTA) was present from doses of 2.5 nmol/kg PYY. Peripheral administration of 300 nmol/kg PYY significantly decreased food intake and led to significant changes in blood pressure. This dose also produced a trend for increased latency to feeding, and decreased activity. In c-Fos studies, peripheral administration of 300 nmol/kg PYY increased neuronal activation in several nuclei of the mesocorticolimbic pathways, and the area postrema (AP). Signalling in these pathways may mediate the aversive properties of PYY, while the AP may detect concurrent alterations in cardiovascular parameters. Feeding studies in fasted animals identified 10 nmol/kg as the minimally effective anorectic dose of GLP-1. Food intake was significantly reduced by 300 nmol/kg GLP-1, including decreased intake in the first feeding bout and a trend for increased latency to feeding. The same dose significantly depressed ambulatory activity and increased heart rate. A CTA was not established following peripheral GLP-1 administration at any dose tested, though patterns in activity and feeding would suggest that aversion was present at high doses. A dose of 300 nmol/kg GLP-1 increased neuronal activation in several areas important in the acquisition of aversion, including the central nucleus of the amygdala (CeA), nucleus of the solitary tract (NTS) and the mesocorticolimbic system. Activation of brain regions by high doses of PYY and GLP-1 correspond to neuronal activation by administration of LiCl. However, 32 mg/kg LiCl increased activation to a far greater degree, suggesting a distinction between substances that reduce food intake purely by aversion, and those that have endogenous homeostatic functions. The effects of GLP-1 and PYY on appetite and aversion are complex, but likely represent separate systems that are activated differentially by different circulating levels of these hormones. By collaborating with the Mathematical Department, Imperial College London, we hope to develop a mathematical model that distinguishes between specific satiety and aversive behaviours. Further work is now required to determine the utility of such modelling in detecting specific appetite inhibitors and reducing animal use.
Supervisor: Murphy, Kevin Sponsor: National Centre for the Replacement ; Refinement ; and Reduction of Animals in Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral