Grant: Project Grant

Tirzepatide is a new medication, currently used to treat people with type 2 diabetes (T2DM). It works on two special cell sensors called (GIP) and (GLP-1). Therefore, it is called dual (two) target-therapy. In addition to its effect on lowering glucose, it is successful in decreasing weight. In animals, using the two-target therapy resulted in more weight loss than using a single therapy alone. Compared with a single-target GLP-1 drug, in humans the two-target therapy resulted in better diabetes control and more weight loss. The way in which this drug works is not fully understood. While this medication reduces eating, the great weight loss cannot be explained only by consuming less food. Obesity results from an imbalance of 'energy in' (food eaten, and food energy extracted in the intestines) and 'energy out' (basal metabolism, energy required to digest food and for physical activity). In our body, there are two types of fat tissue: white fat stores excess food energy causing obesity, and brown fat uses the food energy to produce heat as part of basal metabolism and decreases weight. Bacteria in the intestines also affect how much energy is extracted from food. We will study the effect of this new two-target therapy over 8 weeks in 80 individuals with obesity but without diabetes. One group will take the new drug once every week, and the other will take a GLP-1 drug, semaglutide. Participants will stay in a special room (with a bed, desk, chair, sink and toilet) for 24 hours to measure their 'energy out' and understand how the new drug is changing it. We will also measure food energy intake and hunger. Special scanners will be used to measure white and brown fat, and how the drug changes their amounts. To understand if the new drug can change the normal bacteria in the gut, we will take samples of feces over time. We believe this research can help us understand how people lose weight with this group of drugs and it can advance the science of treating obesity.