Genetic and biological evidence indicates that the MG molecule might function to gather, concentrate and present antagonists that block the function of certain weight-regulating melanocortin receptors, thereby enhancing the receptors' signaling, explains Dr. Moore. In agouti-yellow mice, which were used in the Millennium study, the agouti gene overexpresses its protein product, which is such an antagonist, thereby blocking the melanocortin receptor, and the mice can become obese. However, the mutant mg gene suppresses this weight gain, keeping agouti-yellow mice at normal weight, perhaps by preventing effective antagonism by the agouti gene product.
Alternatively, the scientists suggest, the MG protein itself may be a signaling receptor, but they are unsure about how MG may function in this mode.
"Because the desired affect is obtained when the mahogany gene is defective, we are optimistic about using the protein for obesity drug development. In developing a drug, it is always easier to decrease gene function rather than to try to increase it," says Dr. Moore.
The strong similarity between the mouse and human genomes should enable the use of the MG protein as a target for screens that test the function and effectiveness of different compounds for possible human obesity therapies.
"The targetability of the mahogany protein offers us an excellent opportunity to
pursue the development of a small molecule that could attach to a receptor and
affect the protein's function. If succes
Contact: Marion E. Glick