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Title: The role of melanocortin pathways in the mesocorticolimbic system in the regulation of energy homeostasis
Author: Banks, Katherine Anne
ISNI:       0000 0004 6059 1471
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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The increasing worldwide incidence of obesity presents a significant economic burden on healthcare resources. The recent obesity epidemic may be attributed to the increasing availability of high fat and high sugar foods in our modern environment. These foods are energy dense, and are thus processed by the mesocorticolimbic system as rewarding substrates. The increased hedonic experience encoded by the activation of the mesocorticolimbic system during consumption of these energy dense foods may result in overconsumption. This may result in non-homeostatic energy intake, precipitating obesity. Melanocortins are neuropeptides which signal anorectically to reduce food intake and increase energy expenditure. Preliminary data within our group found that intra-ventral tegmental area (VTA) melanocortin administration reduced acute food intake in ad libitum fed rats. The work described in this thesis has determined that this effect is mediated via the melanocortin 4 receptor (MC4R), and is dependent on both nutritional status and diurnal phase. Furthermore, melanocortins were found to reduce acute food seeking behaviour in mice. Intra-VTA administration of melanocortins resulted in the increased activation of neurons in both the VTA and downstream mesocorticolimbic areas, including the nucleus accumbens shell, amygdala, lateral septal nuclei, ventral pallidum (VP) and the prefrontal cortex. Finally, the restoration of MC4R signalling in specific regions of the mesocorticolimbic system of MC4R null mice was used to investigate the role of MC4R in reward and energy homeostasis. Restoring MC4R signalling in the VP decreased chronic food intake but had no effect on body weight. General activity was decreased in these mice, suggesting melanocortin signalling in the VP plays a role in activity and energy expenditure. These findings suggest that melanocortin signalling in the mesocorticolimbic system may serve to maintain energy homeostasis and thus prevent the development of obesity. Further work is required to characterise the specific neuronal circuits responsible.
Supervisor: Murphy, Kevin ; Ungless, Mark Sponsor: Medical Research Council ; British Pharmacological Society
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral