Semenkovich is known for his research on lipid metabolism, obesity and atherosclerosis. His laboratory has developed several mouse models in which genes are deleted only in selected tissues, such as the liver or blood vessels. Much of his research has involved a protein known as uncoupling protein-1. In muscle tissue, uncoupling protein-1 converts the energy from food into heat and mimics the effects of exercise. Making more of it prevents obesity in mice, as well as many age-related diseases.​