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
