Grant: Project Grant

Our bodies rely on 3 major fuel sources we obtain from the food we eat; fats, sugars, and protein. However, during starvation our livers make a 4th fuel source that our organs (brain, heart, and muscle are the main users) can use to make energy, the ketone body. Past research has heavily focused on understanding the regulation of fat, sugar, and protein metabolism in health, and how they malfunction in various diseases such as obesity and diabetes. The regulation of ketone body metabolism in health and disease has received much less attention. However, exciting data in our lab has shown that decreasing the muscle's ability to burn ketone bodies for energy improves blood sugar control in obesity/diabetes. The major goal of our research project is to understand how decreasing the muscle's ability to burn ketone bodies for energy improves blood sugar control. In order to test our hypothesis, our lab has generated genetically modified mice that have reduced metabolism of ketone bodies only in their muscles. We have identified a number of potential factors that may explain the improved blood sugar control in these animals, which includes; (1) general increases in a protein modification known as succinylation, (2) activation of a global energy sensor protein, and (3) enhanced sugar metabolism. We will use both drugs and genetic approaches to independently reverse these 3 changes in our animals, in order to determine whether they counteract the improved blood sugar control we have observed during obesity/diabetes. In summary, our research may lead to the discovery of a new approach to improve blood sugar control in obesity/diabetes, while defining how this improvement takes place at the cellular level.