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Title: Investigating the physiological role of glucokinase in central glucose sensing
Author: Holton, Christopher
ISNI:       0000 0004 5361 3935
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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The brain is dependent on a constant supply of glucose as its primary fuel. Consequently, the brain has developed ways to tightly control intake of glucose, via glucose sensing neurones containing the enzyme glucokinase (GK). This thesis identifies a role for a subset of glucose sensing neurones in the arcuate nucleus (ARC) of the hypothalamus to promote glucose intake. These neurones form part of a pathway separate to the control of peripheral glucose homeostasis. Direct injection of a GK activator into the ARC increases glucose intake. Stereotactic injection of recombinant adeno-associated virus containing GK antisense (rAAV-GKAS) into the ARC of rats chronically decreases GK activity compared to controls. Knockdown of ARC GK reduces glucose intake in an acute and long-term setting. Direct injection of an ATP-sensitive potassium (KATP) channel inhibitor into the ARC increases glucose intake in a similar manner to that of a GK activator. In addition, pre-treatment with a KATP channel activator attenuates the orexigenic effect of a GK activator. ARC glucose sensing neurones are likely mediated by neuropeptide Y (NPY) as both activation of GK and inhibition of KATP channels stimulate NPY release in hypothalamic explants. Also, pharmacological inhibition of Y1 and Y5 receptors, and P/Q type voltage gated calcium channels, attenuate the orexigenic effect of GK activators. ARC glucose sensing neurones represent a novel pathway that may be part of a mechanism to ensure adequate glucose is constantly available to the brain. This work suggests that ARC GK has a physiological role in the homeostatic regulation of glucose intake. ARC GK responds to periods of fasting and may contribute to an increased preference for glucose. Thus, ARC glucose sensing may drive dietary sugar intake, which may be a contributing factor in obesity.
Supervisor: Gardiner, James; Dhillo, Waljit Sponsor: Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral