| In recent years, the central melanocortin system has been assigned a prominent position in the model of the neural circuitry that controls energy homeostasis. Dozens of pharmacological studies have shown that activation or blockade of melanocortin 3/4 receptors (MC3/4-R) alters feeding and energy expenditure. Previous research in this area has focused on hypothalamic MC3/4-R, but these receptors are also expressed in caudal brainstem nuclei of relevance to energy balance. The four studies presented in this dissertation broadly address the contribution of hindbrain MC3/4-R to the control of energy balance. First, we confirm that there is a brainstem MC3/4-R trigger for both feeding and energy expenditure responses. Significant effects on feeding behavior were obtained after injection of very low doses of MC3/4-R ligands directly into the dorsal vagal complex in the caudal brainstem (anorexia after MTII, an agonist, and hyperphagia after SHU9119, an antagonist). Energy expenditure was elevated in both chronic decerebrate rats and their neurologically intact controls in response to 4th-icv injection of MTII, as indicated by increased uncoupling protein 1 gene expression in brown adipose tissue. We also provided a detailed characterization of the behavioral responses to 4th-icv MTII and SHU9119 treatment. For MTII, we demonstrated an inhibition of meal size, and discounted the possibility that the anorexia seen in response to this treatment is secondary to motor disruption. For SHU9119, we identified an interaction between physiological state (i.e., food deprivation) and drug-induced hyperphagia. An overall judgement derived from these experiments is that the profile of responses to caudal brainstem MC3/4-R agonist or antagonist treatment mirrors that obtained with hypothalamic treatment. The results, thereby, provide a counterpoint to the prevailing hypothalamocentric perspective. It is argued that the current model of central energy balance control should be expanded to describe two parallel systems, one in the hypothalamus and one in the caudal brainstem, and that research should begin to focus on interactions between these regions. |
