Leptin and insulin signaling in the hypothalamus are key to the central regulation of glucose and energy expenditure. Of particular importance is PI3K signaling in the ventromedial hypothalamus (VMH), a brain region central for the regulation of sympathetic outflow. Our preliminary results reveal the complex nature of PI3K signaling, with multiple subunits, each responsible for different aspects of energy homeostasis. Within this application we have developed novel mouse genetic tools to study the physiological requirements for the PI3K pathway and leptin signaling in anatomically identified SF1 neurons. Furthermore, we will examine how these pathways converge to mediate the beneficial effects of exercise. Together, these studies will increase our understanding of the biological control of energy balance, how it relates to exercise, and will provide mechanistic insights to the effectiveness and safety of newly approved anti-obesity drugs.
The aim of this proposal is to gain a deeper understanding of how the brain regulates glucose, insulin, lipids, and energy expenditure to meet various metabolic challenges, including high calorie diets and physical exercise.