AbstractsBiology & Animal Science

The prevalence of obesity has increased alarmingly over the last several decades, and it continues to be a cause of concern across the globe. Physical activity, including non-exercise activity thermogenesis (NEAT), is a crucial factor that accounts for individual differences in body weight, interacting with one's genetic predisposition. The brain mediates energy homeostasis via a number of neuroendocrine intermediates that regulate food intake and energy expenditure (EE) such as the brain melanocortin (MC) system. In arcuate nucleus, the prohormone pro-opiomelanocortin (POMC) is cleaved into several bioactive peptides including a-MSH, which bind to MC receptors (MCR). Of the five known receptors, MCR1 through 5, MC3R and MC4R have emerged as critical modulators of EE and food intake. To determine how MC signaling may differ in association with high and low EE and physical activity, we used rats artificially bred for high and low intrinsic aerobic capacity. HCR (high capacity runners) and LCR (low capacity runners) rats are established animal models for leanness and obesity, respectively. HCR rats also have high EE and activity, independent of differences in body weight. Focusing on different nuclei of the hypothalamus and isolating tissues by micropunching as well as by laser capture microdissection, I have identified brain region-specific differences in the expression of MCR 3, 4, and also MC5R between the obesity-prone, low-activity vs. the obesity-resistant high-activity rats. Further, by using receptor-specific agonists and antagonists, it was observed that the differences in activity and associated EE as a result of MCR activation or suppression were similarly region-specific and directly corresponded to the differential expression patterns of MCR subtypes in hypothalamic nuclei. However, in the nuclei and receptor subtype examined, I did not detect an effect on food intake as a function of MCR activation or suppression, which suggests that while receptor-mediated function is critical, it is not involved in all components of energy balance regulation. Taken together, these data implicate region-specific MCR activation in differences in physical activity, (but not necessarily food intake). Thus, MCR-mediated physical activity may be a key trait in distinguishing the lean phenotype and a target for enhancing physical activity and NEAT.