In 1994, scientists discovered the first mechanism by which a defect in a single gene could cause obesity in mice. That gene directs the production of leptin, a hormone in fat cells that regulates aspects of eating and metabolism. Now, scientists at Oregon Health Sciences University have discovered how another gene, called agouti, causes a form of obesity in mice which has greater similarity to human obesity. Their findings appear in the Jan. 9, 1997 issue of the journal Nature and shed light on molecular events that may underlie obesity in humans.
"The mouse is proving to be a valuable resource for elucidating the molecular and genetic basis of body weight regulation," says Roger Cone, Ph.D., scientist at OHSU's Vollum Institute and senior author of the paper. "Our team recently discovered how a mutated agouti gene leads to overeating and excess body fat in mice. The mice develop a moderate form of obesity rather than the morbid kind of obesity induced by some of the other mouse genes associated with obesity that have been discovered to date. Most humans that are overweight are moderately heavy, not morbidly so. This discovery helps pave the way for the design of therapeutic drugs to treat common forms of human obesity."
Though its role in feeding was just recently uncovered by OHSU scientists, the agouti gene has long been known to cause a yellow coat color in mice and other animals by blocking the production of dark pigment called melanin in hair follicles. The agouti gene does this by blocking a key receptor on the surface of pigment cells. This receptor is called the MSH receptor and is responsible for stimulating melanin production.
"However, certain mutant forms of the agouti gene are expressed not only in hair follicles, but in every cell of the mouse's body, including key regions of the brain that influence feeding behavior," says Cone. "Whereas the normal agouti gene does not play a role in feeding behavior, mutated forms of the gene inadvertently disrupt signaling pathways in the brain that influence the animals desire to eat too much."
Mutated forms of the agouti gene produce excess amounts of a protein that blocks the MSH receptor on brain cells. Blocking the MSH receptor interferes with a hormonal signaling pathway in the hypothalamus of the brain, a region known to govern basic drives such as feeding.
"In brain cells, the MSH receptor serves different functions than it does in hair follicles," says Cone. "In the brain, the MSH receptor influences feeding behavior. When mutated forms of the agouti gene are inappropriately expressed in the brain, normal feeding behavior is disrupted and the mice become obese and develop symptoms of diabetes."
The animal overeats because the mutant agouti gene interferes with a key signaling pathway that tells the animal to stop eating. This signaling pathway involves an important hormone called melanocortin. In the normal mouse brain, when melanocortin binds to a particular kind of MSH receptor, called the MC4 receptor, it exerts an inhibitory effect on eating and causes the animal to stop feeding. So normal mice do not get fat.
However, the mutated agouti gene prevents melanocortin from binding to the MC4 receptor. Animals with the mutated agouti gene fail to receive an inhibitory signal from the brain, and they consume excessive amounts of food.
In a supporting paper to appear in an upcoming issue of the journal Cell, scientists at Millennium Pharmaceuticals in Cambridge, Mass., with help from Cone's team, show that specially bred mice lacking the MC4 receptor overeat just like the agouti mutants. "This points to the blocking of the MC4 receptor as the primary mechanism of obesity induced by the agouti gene," says Cone.
To date, five genes have been discovered in the mouse that influence obesity. Known as tubby, fatty, diabetes, obesity and agouti genes, each has a different molecular mechanism for causing obesity. "Agouti was the first obesity gene cloned in the mouse," says Cone. "A graduate student in my lab, Dongsi Lu, was the first to pharmacologically characterize the agouti peptide and determine how it influences pigmentation, and we have now determined the mechanism by which certain mutant forms of the agouti gene cause obesity."
Members of the research team involved in the recent discovery of how the mutated agouti gene causes obesity include Wei Fan, Ph.D., a visiting scientist from China; Robert A. Kesterson, Ph.D., a postdoctoral researcher at OHSU's Vollum Institute; Bruce Boston, M.D., an assistant professor of pediatric endocrinology at OHSU; and Victor Hruby, a chemist at the University of Arizona.