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Title: To investigate the physiological role of arcuate nucleus cocaine- and amphetamine-regulated transcript in energy homeostasis
Author: Campbell, Daniel Charles
ISNI:       0000 0004 2694 1255
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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Cocaine- and amphetamine- regulated transcript (CART) was originally identified as a mRNA transcript upregulated in rats in response to administration of cocaine and amphetamine. CART is widely expressed in the central nervous system (CNS) with high levels of expression in hypothalamic nuclei such as the arcuate nucleus (ARC). CART was initially thought to act as an anorectic peptide since it is coexpressed with the anorectic neuropeptide pro-opiomelanocortin (POMC) in the ARC. In addition, intracerebroventricular (ICV) administration of CART (55-102) peptide inhibits feeding and administration of anti-CART antibody results in stimulation of feeding. However, subsequent studies have suggested CART may also act as an orexigen since injection of CART (55-102) specifically into the ARC and ventromedial nucleus (VMN) of the hypothalamus results in a significant increase in food intake. These data suggest CART acts through both anorectic and orexigenic circuits. Given the importance of the hypothalamus in the regulation of energy homeostasis, and the role of the ARC in integrating peripheral signals, it is essential to elucidate the role of ARC derived CART. In order to elucidate CART’s true physiological role in the ARC I used a combination of genetic approaches. I generated a recombinant Adeno-associated virus (rAAV) expressing CART antisense (CART-AS) and a transgenic mouse model which utilises the POMC promoter to drive expression of CART-AS. In the transgenic CART-AS model mice exhibited a significantly higher body weight relative to control animals, no significant difference in food intake was observed. In addition, mice expressing the CART-AS transgene demonstrated a reduction in uncoupling protein-1 (UCP- 1) mRNA expression in brown adipose tissue (BAT) which is suggestive of decreased thermogenesis. This may explain the observed increase in body weight in the transgenic mice. Bilateral intra-ARC injections of rAAV-CART-AS resulted in a significant increase in cumulative food intake and body weight gain compared to control animals. There was no significant difference in activity or metabolism levels. The data presented in my thesis provides an important contribution to understanding the role of CART within the ARC. The results from my genetic studies appear to suggest that ARC derived CART has an anorectic role.
Supervisor: Gardiner, James Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral