They then identified the receptor as prohibitin, a protein which is known to regulate cell survival and growth. "The expression of prohibitin in organelles inside the cells such as the mitochondria, and the nucleus, has been established, but its presence and function on the cell surfaces of blood vessels associated with white fat tissue has not been explored," says Arap. "We don't know what prohibitin is doing there, but we know that this protein is not normally found in blood vessels of several other tissues and also of tumors derived from fat tissue."
Once that they had a "docking receptor" specific to white fat tissue, the researchers designed a drug. They created a synthetic ligand - a sequence of amino acids that would fit neatly into the prohibitin receptor, like a key into a lock - and fused to it a corkscrew-shaped "drug" that they knew could induce a cell to self-destruct.
"We have previously shown that this drug can be targeted to blood vessel cells of tumors of the prostate in mice, resulting in reabsorbtion of these tissues due to oxygen deficiency," says Pasqualini.
"The ligand - the guidance system - brings the therapeutic drug to the prohibitin receptor, where it locks on, and then is internalized into the blood vessel cell," she says. "It selectively destroys these blood vessels."
In a series of experiments, the investigators found that one month of treatment in severely obese mice was enough to restore the animal's normal body weight. None of the mice used in the therapy experiment were genetically altered or prone to obesity prior to treatment; they gained weight because they ate a high-fat diet.
The authors then conducted other experiments to make sure that the animals were not loosing weight because of nutrient malabsorption or appetite suppression. They note that there were
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9-May-2004