Grant: Project Grant

Obesity and eating disorders are known to lead to pathological changes in metabolism, diabetes and cardiovascular disease, and are significant and growing health problems in western societies with a very high burden on individual health and the health care system (http://www.cdc.gov/obesity/data/facts.html). Despite intensive investigation and steady advances in our knowledge about the ways in which appetite and eating are regulated by the brain, we still do not fully understand how these behaviours are controlled, nor why and how this control can go wrong and then lead to disease. Consequently, there are currently very few effective treatment methods. Further study and new insights are necessary to combat this escalating health problem. The objective of this proposal is to investigate detailed cellular mechanisms that underlie a central and essential pathway in the brain - the melanocortin pathway - that controls eating behavior. Our proposal takes advantage of very recent discoveries in my laboratory that suggest a completely new way in which the melanocortin pathway works inside cells of a particular region in the brain, called the hypothalamus. We have shown that when a special protein that transports calcium out of brain cells, NCKX4, is not working in mice, those animals eat much less and weigh less. We have also shown that this is because the receptor protein, MC4R, that starts signaling in the melanocortin pathway, uses calcium to work. With these new ideas as a starting point, we will test exactly where and how the melanocortin pathway works. The experiments proposed here will lead to an in-depth understanding of the cellular signals that control feeding behavior, satiety and obesity. This information will be critical in understanding normal feeding behaviour and the events that underlie its dys-regulation. This information has the potential to lead toward the development of novel, much needed, therapeutic agents for eating disorders.