3/10/99
MEDIA CONTACT: Kristin Weidenbach, (650) 723-0272 or (650) 723-6911, [email protected]
FOR COMMENT: Gregory Barsh, MD, PhD, (650) 723-5061, [email protected]
GRAPHICS: A photo comparing a normal mouse with a mutant mahogany mouse can be obtained by contacting Walter Hangad (650) 723-7897 or (650) 723-6911, [email protected]
STANFORD SCIENTISTS DISCOVER MOUSE GENE THOUGHT TO INFLUENCE APPETITE AND ACTIVITY
STANFORD -- In an effort to develop a drug to combat obesity, researchers have long sought to find a gene that controls weight. The discovery of the defective agouti gene, which can cause mice to swell up to three times their normal size, heralded a new era in body weight research. The 1992 finding was followed two years later by discovery of the human fat-regulating gene leptin. But a pill to combat obesity has remained tantalizingly beyond reach. Scientists may now be one step closer to developing therapies to regulate the genetic factors that play a role in obesity, following the discovery by Stanford researchers of another mouse gene involved in appetite and activity. Mice lacking the newly discovered mahogany gene eat more and exercise more than normal mice.
"The mutation interferes with both metabolism and feeding behavior," said Gregory Barsh, MD, PhD, a Howard Hughes Medical Institute investigator and Stanford associate professor of genetics and pediatrics. "Sometimes the mice gain weight and sometimes they lose a little bit of weight, depending on whether overeating is greater than increased activity," said Barsh, senior author of the study that appears in the March 11 issue of the journal Nature.
At this stage, the researchers are not sure which comes first - whether overeating causes the mice's increased activity, if overactivity causes excessive eating, or even if the two behaviors are dependent on one another. It may be that they just happen separately but concurrently, said Barsh.
The mystery deepens when the role of the mahogany gene's human counterpart is considered. A large part of the protein made by the mouse mahogany gene has been found to be 93 percent identical to a human protein called attractin that was recently discovered by Jonathan Duke-Cohan and colleagues at Boston's Dana Farber Cancer Institute. The human protein is produced by activated T cells and is thought to stimulate attraction between cells of the immune system.
At first, researchers thought that the proteins made by the two genes were different - the attractin protein circulates freely within human blood, whereas the mahogany protein appears to be anchored within the membrane of stationary mouse cells.
Barsh and his team decided to further explore the relationship between the mouse gene and the human gene. In doing so, the researchers discovered that there are actually two forms of the human protein: the familiar circulating form of attractin and a second membrane-bound form that is almost identical to the mouse mahogany protein.
The similarity prompted the Stanford researchers to look for a connection. "We have been working together with Jonathan Duke-Cohan's group to try and understand the possible connection between regulation of body weight and immune function," said Barsh.
The mahogany gene is switched on in many tissues, including cells in the skin and brain, and produces a large protein that spans the cell membrane. The external portion of the protein is characteristic of a receptor - a protein that sticks out of the cell membrane to bind passing molecules and transmit information into the interior of the cell. Barsh and his colleagues suspect that the mahogany protein may be helping the agouti protein - which causes weight gain and effects hair color - to bind to the cell surface.
As Barsh and his team continued to study mahogany they found that the portion of the protein protruding into the cell seemed too short to effectively transmit information. They believe that the mahogany protein may be teaming up with a hormone receptor to send signals into the cell.
The hormone receptor mahogany seems to be binding with is found in the skin and the brain. When agouti and/or mahogany proteins bind to these receptors in skin cells, they affect hair color. However, if they erroneously bind with these same receptors in the brain, the researchers believe it may result in the body weight and appetite anomalies found in mice with defective versions of the agouti and/or mahogany genes.
The ability of the mahogany protein to interact with these hormone receptors creates a further link back to attractin, the mahogany-like human protein. While the researchers believe mahogany teams up with the
hormone receptors to send signals into the cell, attractin and other molecules also use these receptors to police interactions between cells of the immune system.
Mahogany appears to be one of many partners in a complex molecular dance, and Barsh cautions that many of the complicated interactions have yet to be unraveled.
The mahogany gene will obviously require further study, but Barsh said it is not hard to imagine that a subclass of obese patients may be found to have an alteration in the mahogany/attractin gene, and that drugs might be developed to correct the problem.
Research for the study was conducted by postdoctoral fellows Teresa Gunn and Arezou Azarani, and by graduate student Lin He. Barsh's co-investigators include Ronald Davis, Stanford professor of biochemistry and genetics, and Stuart Scholssman and Jonathan Duke-Cohan from the Division of Tumor Immunology, Dana Farber Cancer Institute. Funding was provided by the National Institutes of Health and the Howard Hughes Medical Institute.
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