Obesity, referring to having an abnormally high proportion of body fat, has become a health and economic problem in wealthy countries such as the United States. Therefore, intensive investigations have been conducted to determine the factors leading to the positive energy balance between energy intake and energy expenditure. The hypothalamus plays a substantial role in the regulation of energy intake and expenditure. However, it is still not clear how various neuronal systems in the hypothalamus interact to maintain normal body weight and how the dys-regulated interactions may compromise the balance between energy intake and expenditure. In this application we propose to identify interactions between melanin-concentrating hormone- synthesizing (MCH) neurons and hypocretin (Hcrt) neurons in the lateral hypothalamus in the regulation of energy balance and body weight at molecular, cellular and whole animal levels. Both MCH and Hcrt systems are critical players in the regulation of energy balance in animals and humans. The MCH system promotes energy intake and decreases energy expenditure while the Hcrt system promotes both energy intake and expenditure. There has been morphological and functional evidence on the possible interactions between these two systems. However, it is still not entirely clear whether the interaction between these two systems is required in the regulation of energy balance in animals and humans and whether changes in the interaction may lead to altered responses of the brain to the energy status of organisms and compromised energy metabolism. Based on current data we hypothesize that a crosstalk between MCH and Hcrt systems is required to maintain normal body weight. Specifically, we propose that the MCH system requires activation from Hcrt cells to promote energy intake, while MCH neurons may provide a feedback pathway to limit the activity in the Hcrt system to curb energy expenditure and maintain the normal body weight in animals. Since neuronal plasticity plays a critical role in the formation and modification of homeostatic and behavioral functions in animals, it is very likely that the modulation of synaptic function in MCH and Hcrt neurons could be one of the mechanisms underlying the interaction between these two systems. Therefore, three goals of this application are: 1) To test the hypothesis that MCH-mediated food intake requires activation from the Hcrt system in animals.; 2) To interrogate the hypothesis that the MCH system is required to limit activity in the Hcrt system to curb energy expenditure; and 3) To examine whether the imbalance between the activities in MCH and Hcrt cells underlie dys-regulated metabolic status (DIO and anorexia) in animals. The answers to these questions will help address the crosstalk between homeostatic centers in the hypothalamus and the role of the crosstalk in the determination of energy metabolism. We hope that this project will benefit people suffering from diseases/conditions (such as obesity and anorexia) resulting from impaired regulation of energy metabolism.
In this application we propose to identify interactions between MCH neurons and hypocretin neurons in the lateral hypothalamus in the regulation of feeding behavior and body weight at molecular, cellular and whole animal levels. We hope that the results from the studies proposed in this application would benefit people suffering from diseases and conditions (such as obesity and anorexia) resulting from impaired regulation of energy metabolism.
