Abstract: A novel uncoupling protein, which we have designated UCP-4, that is expressed in various tissues, including brain, heart, pancreas, and muscle tissue, and nucleic acid molecules which encode for said novel protein, are described. Methods of screening for compounds that regulate the expression and the activity of UCP-4 are described, as well as methods of treating diseases or conditions in which the regulation of thermogenesis or respiratory ATP synthesis is desired. Such conditions include obesity, diabetes, malignant hyperthermia, and fever. The construction of cell lines that express UCP-4 is also described.