Stanford,
CA (3/12/99)- The discovery of a new gene involved in appetite control
and regulation of body weight could open the way for new treatments for obesity,
report two research groups.
The mahogany, or mg, gene was identified in mice, and is related
to agouti, a gene that causes skin pigmentation and obesity in the
'agouti mouse', one of a number of types of mutant mice used in obesity studies.
Mice with a mutation in their mg gene maintain a healthy weight whether
they eat a high fat or low fat diet with the same amount of calories. In contrast,
mice with a normal mg gene gain excess weight on the high fat diet.
Photo: Mice
with a mutation in their mg gene, such as the thin mouse, maintain
a healthy weight whether they eat a high fat diet or a normal, low fat diet.
Mice with a normal mg gene, such as the plump mouse, gain weight when
they eat a high fat diet.
"The mutation interferes with both metabolism and feeding behavior. Sometimes
the mice gain weight and sometimes they lose a little bit of weight, depending
on whether overeating is greater than increased activity," said Gregory Barsh,
MD, PhD, a Howard Hughes Medical Institute investigator and Stanford associate
professor of genetics and pediatrics.
The protein encoded by the mouse mg gene is nearly identical to attractin,
a human protein that is produced by activated T cells and appears to be involved
in stimulating attraction between cells of the immune system. The researchers
were puzzled by this apparent discrepancy, wondering what could be the connection
between a protein with an immunological function and a very similar protein
that appears to regulate appetite. Further investigation revealed there were
in fact two forms of the human attractin protein: the immune system modulator
found in a circulating form, and a second membrane-bound form that is almost
identical to the mouse mahogany protein.
The Stanford researchers determined that when activated, the mg gene
produces a large protein that spans the cell membrane. The protein looks like
it may be a receptor facilitating communication between molecules outside
of cell membranes and the cell interior. In particular, it appears that the
mahogany protein may be helping the agouti protein, known to cause weight
gain, to bind to the cell surface.
Interestingly, both proteins also appear to be involved in hair color determination
when they interact with receptors on skin cells. The researchers believe that
the the proteins may on occasion erroneously bind with receptors in the brain,
resulting in body weight and appetite anomalies.
In related research, scientists at Millennium Pharmaceuticals report they
have cloned the mg gene. They discovered that the the gene is active
in a specific region of the brain's hypothalamus associated with body weight
regulation.
"The cloning of the mahogany gene and the identification of its protein product
are major first steps in achieving a better understanding of their roles in
controlling weight based on the amount of fat in a diet. "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," said Karen Moore, Ph.D., director of genetic systems at the biotechnology
company.
While much remains to be elucidated about the function of the mg gene and
its relationship with other genes associated with metabolism the researchers
believe the similarity between the mouse gene and its human counterpart will
enable the use of the mahogany protein as a target for screens that test the
function and effectiveness of different compounds for possible human obesity
therapies.
Both studies appear in the March 11,1999 issue of the journal Nature.
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