Texas scientists have identified two hormones that tell the brain it is hungry, a discovery that should make it possible to design new drugs to treat both obesity and anorexia.
The hormones, discovered in rats but thought to be present in all species, respond to metabolic signals, such as low levels of sugar in the blood, by stimulating appetite.
The researchers, who announced the discovery today in the journal Cell, are looking for drugs that can block the hormones' activity, in the hope of finding effective new weight-loss drugs. The paper's publication is expected to spur a frenzy of activity at drug companies searching for a magic bullet for obesity.
"It's an absolutely beautiful piece of work," said Dr. Jeffrey Friedman of Rockefeller University, who recently discovered another obesity-related hormone called leptin.
The isolation of the hormones, called orexins after the Greek word for appetite, is "a technical tour de force," said Dr. Jeffrey B. Flier of the Beth Israel Deaconess Medical Center in Boston.
The discovery began when the research team led by Dr. Masashi Yanigasawa of the Howard Hughes Medical Institute at the University of Texas Southwestern Medical Center in Dallas stumbled across two receptors in cells from the lateral hypothalamus of rat brains. Receptors are sites on the cell surface that bind specific molecules, such as hormones.
These were called orphan receptors because nobody knew what binds to them. Because the lateral hypothalamus is the portion of the brain that is known to control appetite, it seemed reasonable that the receptors would be involved in that process.
The team ground up large quantities of rat brain and fished through it to find molecules that would bind to the receptors. They eventually isolated two closely related proteins called orexin-A and orexin-B. Their structures, Yanigasawa said, are unlike any hormones previously known.
When the Texas team injected small quantities of the hormones into the brains of rats, the animals ate voraciously, consuming eight to 10 times the normal amount of food in the first hour or two. When the team starved rats for a day, larger than usual amounts of the hormones built up in the hungry animals' brains.
"We now believe that orexin is one of the important pathways in the regulation of hunger," Yanigasawa said.
But Dr. Michael Schwartz of the University of Washington and the Puget Sound VA health care system cautioned that "we have seen other hormones that looked good and didn't pan out. Many groups around the world will start looking at these to try and figure out if they really are important or not."
The researchers also identified the gene that serves as a blueprint for production of the two hormones. That gene orders the production of a larger protein called prepro-orexin. Enzymes within the cell then cut off different sections of prepro-orexin to produce either orexin-A or orexin-B.
The compilation of all this information into one journal article is a remarkable task, Schwartz said. He noted that it took more than 10 years for various groups of researchers to discover the same amount of information about another appetite-related hormone, called neuropeptide Y, after it was discovered in 1983.
"Now, in this one paper, we have the discovery of a new system, we know something about its receptor, about its effects on food intake and about its regulation," Schwartz said. "It shows what a good laboratory using state-of-the-art techniques can do."
The challenge now is to find drugs that can mimic or block the new hormones' effects. Mimicking drugs, for example, could be used in treating anorexia, a disorder in which young women do not eat enough and become emaciated. The drugs could also be used to counteract the wasting effects of such diseases as cancer and AIDS.
The real gold mine would be in finding drugs that block the orexins' effects, thereby reducing appetite. More than 58 million Americans, a third of the adult population, are classified by the government as obese, meaning that their weight is more than 20% above recommended levels.
Such people would welcome a safe drug that would help them lose weight. These drugs would be especially valuable to people with medical conditions, such as Type 2 diabetes or heart disease, that are best treated with weight loss.
Another task confronting researchers is to determine how the orexins interact with other hormones, such as leptin and neuropeptide Y. Leptin was considered particularly promising when it was discovered in 1995. Researchers found that it could produce large weight losses in genetically obese mice.
But further studies have shown that leptin levels and regulation in obese humans are apparently normal and public interest in that hormone has waned.
Yanigasawa suspects that leptin may be the chemical that stimulates production of orexins, but that has not yet been proved. "That is something that we have to study from now on," he said.