Role of CART in food intake and energy homeostasis

Cocaine- and amphetamine regulated transcript (CART) peptides are widely distributed throughout the brain and represent neuronal signalling molecules that are involved in several processes including addiction, reward, stress responses and anxiety. Importantly, the highest abundance of CART is found in hypothalamic nuclei, a brain area which is crucial for integrating information on energy levels from the body with brain pathways that control energy homeostasis. This distribution suggests a critical function of CART signalling in the control of food intake and energy balance. As a specific CART receptor has remained unidentified, it is impossible to block CART with the help of specific pharmacological tools such as antagonists. Therefore work to decipher the detailed mechanism of CART function has been hampered and the precise role of CART in the control of food intake remains difficult to determine. While CART has frequently been demonstrated to inhibit food intake when administered into brain ventricles, injection of CART into specific hypothalamic nuclei increases feeding and body weight. Hence, there is evidence for an involvement of CART in both appetite stimulating and suppressing neurocircuits, and delivery of CART into the brain ventricles has the major pitfall of non-specific widespread effects of CART. For this reason, the research group of Professor Herbert Herzog has generated new mouse models that circumvent these shortcomings. The use of these new models combined with new sophisticated delivery tools will allow to modify CART levels as well as CART neuron function in a locationally and temporally specific way and enable the detailed analysis of the function of the hypothalamic CART system without the need of knowledge of the CART receptor(s). I hypothesize that CART neurons within the hypothalamic pathways are pivotal in the control of feeding and energy homeostasis and that imbalances in this system can contribute to the development of obesity. The major aim of this proposal is to investigate the specific contributions of different populations of CART neurons in the hypothalamus to the control of feeding and energy balance as well as to investigate other consequences of the modulation of the CART system. Therefore the different mouse models will be investigated in terms of physiological readouts such as food intake, body weight gain, energy expenditure and activity as well as molecular analysis of various organs and tissues including brain and adipose tissue. Since the newly developed mouse models are only available in Prof. Herzogs group, I would like to carry out this research project in his laboratory. The results will provide critical new insights into the complex central regulation of food intake and energy balance and help in the development of potential therapeutics that are needed to treat obesity, a major global public health concern. 1

Cocaine- and amphetamine regulated transcript (CART) peptides are highly expressed in various nuclei of the hypothalamus, a brain area that is crucial for integrating information on energy levels from the body with brain pathways that control energy homeostasis. This distribution suggests a critical function of CART signalling in the control of food intake and energy balance. However, work to decipher the precise role of CART in the control of food intake remains difficult to determine, as a specific CART receptor has remained unidentified. In the present project, a new mouse model was combined with new sophisticated viral delivery tools, which allowed to modify CART levels as well as CART neuron function in a spatial and temporal specific way enabling the detailed analysis of the function of the CART system in the hypothalamus. Our results show that the impact of CART on food intake and energy homeostasis is highly dependent on its site of action. Thus, introduction of CART into the arcuate nucleus of the hypothalamus decreased fat mass and body weight, whereas energy expenditure and physical activity were increased. While food intake was not affected, the expression of neuropeptide Y, a neuropeptide that is involved in the development of obesity, was decreased. In contrast to these findings, introduction of CART in the lateral hypothalamus caused an increase in fat mass, that was associated with an increase in food intake, reduced energy expenditure and impaired glucose tolerance. Furthermore, the expression of corticotropin-releasing hormone was increased, a factor that is not only crucial for the stress response, but also exerts metabolic effects. In addition to these effects of chronic introduction of CART, acute activation of CART neurons in the lateral hypothalamus increased physical activity, energy expenditure, body temperature and food intake. CART neuron activation further increased markers of neuronal activation in several brain areas that could underlie the observed effects. As most of these effects could also be observed in the absence of endogenous CART, these results give insight into the effects of CART per se as well as the effects of other neurotransmitters that are co-expressed with CART in these neurons. In summary, it can be concluded that the effects of CART can be both anabolic and catabolic depending on its site of action within the brain and that its actions are integrated in complex neurocircuits that control energy homeostasis.