Obese individuals must enter negative caloric balance to reduce adiposity. Negative energy balance activates homeostatic mechanisms that appear to defend body weight. Thus, reduced caloric intake is associated with altered autonomic outflow producing concurrent reductions in energy expenditure, heart rate and blood pressure. The purpose of this proposal is to determine the mechanisms by which heart rate and blood pressure are decreased during reduced caloric intake. Substantial evidence supports the hypothesis that decreased circulating leptin signals reduced caloric availability and engages multiple hypothalamic pathways that stimulate appetite, reduce metabolic rate, and lower heart rate blood pressure. However, studies using animals with dysfunctional leptin signaling support the concept of leptin-independent regulation of cardiovascular function during negative energy balance. Therefore, the first aim of the proposal is to determine if leptin signaling is requisite for cardiovascular and thermogenic responses to reduced caloric intake. The approach will be to continuously determine oxygen consumption via indirect calorimetry and heart rate and blood pressure using telemetry, while infusing low levels of leptin peripherally during caloric restriction. Genetically altered mice have contributed significantly to understanding the potential mechanisms regulating energy balance. Thus, we will utilize both rat and mice models to accomplish the aims of this proposal. In the second aim, we propose to test the hypothesis that glucose sensitive neurons within the hypothalamus are requisite for normal regulation of energy expenditure and cardiovascular function during negative energy balance. In the third aim, we will test the hypothesis that inhibition of melanocortin receptors within the hypothalamus is requisite component of the cardiovascular effects of negative energy balance. Finally, we will examine the role of melanin concentrating hormone in the regulation of cardiovascular and metabolic responses to reduced caloric intake. Taken together, these studies will greatly enhance our understanding of the interrelationship between the regulation of energy balance and cardiovascular function and will have important implications for treatment of obesity and hypertension.
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