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Title: Investigating the role of central nutrient-sensing neurones using adeno-associated viral manipulation of glucokinase
Author: Richardson, Errol
ISNI:       0000 0004 2710 2701
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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The primary aim of the work described in this thesis was to investigate the physiological role of glucose sensing neurones within the arcuate nucleus of the hypothalamus (ARC). To this end, recombinant adeno-associated virus encoding glucokinase (rAAV-GKS) was delivered to the ARC of adult male Wistar rats. Glucokinase (GK) catalyses the first reaction in glycolysis and has been hypothesised to act as a regulator of hypothalamic glucose sensing. Furthermore, manipulation of GK has been shown to alter the sensitivity of glucose sensing neurones in vitro. I hypothesised that increasing GK expression in the ARC using rAAV-GKS would influence the sensitivity of glucose sensing neurones in vivo and provide insight into their physiological role. Bilateral administration of rAAV-GKS to the ARC resulted in a 14-fold increase in hypothalamic GK mRNA expression compared to controls. Food intake and body weight gain were significantly increased in rAAV-GKS treated rats compared to controls on standard chow. The increased body weight of the rAAV-GKS group was attributed to a significant increase in adipose tissue with no difference in lean mass. Food intake and body weight gain were also significantly increased in rAAV-GKS treated animals maintained on a high calorie “western-style” diet. Despite their increased adiposity, rAAV-GKS treated rats displayed significantly improved glucose tolerance compared to controls. The increased glucose tolerance of the rAAV-GKS group was associated with increased glucose-stimulated insulin secretion. rAAV-GKS treated rats consumed a significantly greater volume of a 10% glucose solution compared to controls over a 16 hour period. In addition, rAAV-GKS animals showed a clear preference for glucose over standard chow compared to controls over 24 hours and during a 31 day longitudinal study. The results of this work suggest that glucose sensing neurones in the ARC may be involved in the regulation of energy balance and glucose homeostasis. These results are of broader significance considering the proposed use of GK activating drugs in the treatment of type II diabetes mellitus.
Supervisor: Gardiner, James ; Bewick, Gavin ; Murphy, Kevin Sponsor: Biotechnology and Biological Sciences Research Council (BBSRC) ; Imperial College Centre for Integrative Mammalian Physiology & Pharmacology (CIMPP)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral