Despite an overall increase in caloric needs, regular physical activity has been associated with improved appetite signaling. The neurobiological mechanisms underlying this sensitization remain unclear. We employed a voluntary wheel running protocol to investigate how physical activity affects gut-brain communication of vagal sensory neurons for the control of feeding behavior in mice. We find that physically active mice exhibit a significant decrease in food intake in response to the delivery of nutrients directly into the stomach, as compared to sedentary controls. Further, sensitivity to cholecystokinin (CCK), a gut-derived satiation factor, is increased in physically active mice. Because CCK’s appetite-suppressing action is known to be mediated by vagal sensory neurons, we currently analyze vagal gut-brain neurocircuits by employing genetic profiling, as well as manipulation and imaging techniques. Together, our results will provide new insights into modulatory role of gut-brain communication pathways in appetite regulation and may provide new targets for body weight control.