Researchers shed new light on why some people overeat

Findings provide information in the war against fat

A new medical discovery may have important implications in understanding eating habits and weight gain Researchers at the University of Michigan Medical Center and the Stanford University School of Medicine are reporting in the Oct. 3 issue of the journal Science the isolation of a new gene that regulates human feeding behavior and body weight.

The gene, named agouti-related protein, is believed to play a major role in brain centers that control feeding behavior. The protein is thought to act by blocking a receptor that mediates satiety or feelings of fullness. This receptor — the melanocortin-4 receptor –has previously been shown to play a major role in regulating body weight.

Feeding behavior in all animals, including humans, is controlled by hormones that act at receptors in feeding centers in a portion of the brain called the hypothalamus. The discovery of this new protein was the result of a collaboration between research teams lead by Ira Gantz, M.D., an associate professor at the University of Michigan and Ann Arbor VA Medical Centers, and Gregory Barsh, M.D., associate professor of pediatrics and genetics at the Stanford University School of Medicine.

“This protein appears to function as an antagonist of hormonal activation of the melanocortin-4 receptor,” says Gantz. “Hormonal activation of this receptor tells a person that he or she has had enough to eat.” Gantz, a surgeon and molecular biologist, was the first to isolate the melanocortin-4 receptor several years ago. Subsequent research by others demonstrated that it is a major brain receptor involved in the control of body weight.

This concept originally arose by studying a rodent model of obesity — the so called “agouti mutant mouse”. Agouti is a protein normally involved in determining mammalian coat color by blocking the melanocortin-1 receptor. However, in the agouti mutant mouse, the protein is abnormally manufactured in all tissues of the mouse. Recombinant agouti protein has also been demonstrated to block, not only the melanocortin-1 receptor, but also the melanocortin-4 receptor. Researchers hypothesized that the abnormal action of agouti at the melanocortin-4 receptor in the hypothalamus caused the obesity characteristic of this mouse strain.

Recent studies have also shown that deletion of the melanocortin-4 receptor in a genetically engineered mouse causes obesity. Based on these observations, Barsh and Gantz believed that there might be a normally occurring agouti-like protein in the hypothalamus involved in weight regulation.

By searching existing gene databases, Barsh found a gene with sequence similarity to agouti, subsequently named agouti-related protein (Agrp). Barsh then cloned the protein and found that it was expressed in the hypothalamus. Using recombinant genetic engineering, Barsh created a mouse that abnormally produced Agrp in all of its tissues.

As hypothesized, this mouse became obese. Finally, Barsh produced recombinant Agrp protein that was then tested by Gantz and his team at U-M on the cloned human melanocortin receptors expressed in cell lines. It was found to be a very potent inhibitor of hormone action at the melanocortin-4 receptor.

“I would consider this discovery a significant advance in our understanding of what regulates feeding behavior in humans,” Gantz says. Agrp occurs in all humans, but it is not known if levels vary. The melanocortin-4 receptor is one of five cell surface receptors for the melanocortin hormones. The term melanocortin refers to adrenocortocotropic hormone, and alpha-, beta- and gamma-melanocyte stimulating hormones. Cells use hormones to communicate with each other. Within the hypothalamus, these hormones cause a feeling of satiety by stimulating the melanocortin-4 receptor. It is believed that this new protein, Agrp , can block the action of these hormones at the melanocortin-4 receptor, thus preventing the individual from feeling full.

Gantz says researchers now must determine what stimulates the release of Agrp and if Agrp circulates in the bloodstream or just acts locally in the brain. “This, as well as previous studies, has generated intense interest by pharmaceutical companies in using the cloned melanocortin-4 receptor to develop an anti-obesity drug,” Gantz says.