Project 451707

Maintaining normal feeding behaviour is critical for overall health. Elevated or diminished food intake reduces quality of life and lifespan for millions of Canadians each year. The brain acts as the critical regulator of feeding behaviour by sensing and responding to a wide variety of signals. The cues that control feeding can be broadly divided into two classes, the first type are signals that control feeding as part of the body's normal hunger and satiation cycles. We refer to these signals as "physiologic cues". The second type are signals that derive from diseases, infection or similar states and we term these "pathophysiologic cues". While physiologic cues (such as those produced when we eat a meal) produce a pleasant satiation, pathophysiologic cues (such as those produced in disease states such as cancer) cause profound nausea. Interestingly, a brain region called the nucleus of the solitary tract (NTS) responds to both physiologic and pathophysiologic cues and in turn regulates hunger. Using different approaches, we have identified a set of NTS cells that responds to meal consumption which are marked by a gene called Cckbr (we call these cells NTS-Cckbr cells). We have also identified a set of NTS cells that express a gene called Gfral and respond to GDF-15, a cancer-associated pathophysiologic signal (we call these cells NTS-Gfral cells). Now that we have identified distinct NTS cells types that respond to distinct types of stimuli (physiologic vs. pathophysiologic) we propose the study of both these cells to determine their function. Ultimately, we expect that in obesity, there may be a defect in NTS-Cckbr cells and restoring their activity may produce beneficial weight loss. Conversely, we expect that blocking NTS-Gfral activity would prevent the weight loss patients experience in diseases such as cancer.