Grant: Project Grant

Obesity is a long-term disease that affects millions of people and puts major pressure on health care systems. New weight-loss medicines like semaglutide (often known by brand names such as Ozempic or Wegovy) can reduce appetite and help people lose a lot of weight. But there are two big problems. First, people often lose a meaningful amount of muscle along with fat, which can reduce strength, slow metabolism, and make it harder to keep weight off. Second, when treatment stops, many people regain weight, and much of that regain can be fat, leaving body composition worse than before. These two issues muscle loss and rebound weight regain are now major gaps in obesity care. Our research aims to create new peptide medicines that help people lose weight in a healthier and more lasting way by using the orexin system. Orexins are natural body signals that can influence how the body uses energy. Our strategy is to design orexin-based medicines that work mainly in organs outside the brain, so we can support healthy metabolism while avoiding brain-related side effects. We will develop and test two approaches. The first is a single "two-in-one" medicine that combines semaglutide with an orexin component, aiming to keep appetite low while helping the body burn energy and better protect muscle. We will also test whether this approach reduces the tendency to regain fat after stopping treatment. The second is a modified orexin medicine designed to stay outside the brain and support energy use while protecting muscle. We will test these new medicines in obese mice and compare results to semaglutide. Our goal is to move toward safer, longer-lasting obesity treatments that deliver meaningful weight loss while preserving muscle and reducing unhealthy fat regain after treatment.