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Treating Eating Disorders

The discovery of two new hormones gives researchers food for thought
For most of us, food is not only a necessity but also a pleasure--which makes eating disorders, such as anorexia nervosa, bulimia nervosa and binge eating, among the hardest of all mental illnesses to comprehend. They are also among the most difficult to diagnose and cure. Not only do sufferers usually deny that they are sick, but there is not much their doctors can do, short of nutritional guidance and counseling.
Yanagisawa
Image: UT SOUTHWESTERN

MASASHI YANAGISAWA headed a team that discovered orexins, hormones that appear to control appetite.

Soon, though, that may change. Clinicians have found some recent success treating these illnesses with antidepressants, which seem to mitigate the low self-esteem and anxiety commonly seen in eating disorder patients. And this month, scientists discovered two novel hormones that appear to modulate hunger and saity--a finding that may well lead to better prevention programs and medications in the near future.

On February 20, researchers from the Howard Hughes Medical Institute at the University of Texas Southwestern Medical Center announced that they had identified a pair of hormones that influence feeding behavior in rats. A paper appeared in the journal Cell the same day. The group, led by Masashi Yanagisawa, came upon the chemicals largely by chance, using a tactic called "reverse pharmacology."

Instead of identifying a chemical and then locating the receptor it binds to in order to learn what it does, they first looked for "orphan" receptors, or those with no know function. When a receptor binds to its matched protein, called a ligand, it trips a series of cellular signals that turn genes on and off. After extensive searching, the group zeroed in on two receptors produced in the lateral hypothalamus--a region of the brain thought to control appetite. They bathed the receptors in ground-up brain tissues and eventually isolated two ligands--hormones that they christened orexin A and orexin B, after the Greek word orexis, meaning appetite.

To test the idea that these hormones influenced appetite, the researchers used catheters to inject them into the brains of rats. The results were startling: the laboratory animals consumed eight to 10 times more food than normal within a few hours. And when Yanagisawa and his colleagues deprived the rats of food for two days, the animals produced much larger quantitites of orexins in their brain. The investigators further identified a gene encoding yet another, larger protein, called prepro-orexin, and found that cellular enzymes break it apart into orexin A and orexin B.

Obese mice
Image: SCIENTIFIC AMERICAN

OBESE MICE. Hormones such as leptin bring about rapid weight loss in genetically engineered mice--such as these with a gene dubbed tubby--but not in humans.

It is unclear whether these hormones--which appear to represent an entirely new class--have the same activity in humans. Leptin--a hormone discovered three years ago--made headlines when scientists showed it could bring about rapid weight loss in obese mice. But other studies quickly revealed that it did not do the same for people.

Even so, drugs that mimic orexin might help patients with anorexia or other wasting syndromes by increasing hunger. And those that block orexins might help patients struggling with obesity and binge eating.

To that end, the Texas team plans to genetically engineer rodents missing the genes for the two orexin receptors and for prepro-orexin to see if this lack will decrease their appetites. And they intend to find out just how orexins interact with other appetite-related hormones. These include leptin--which is not produced in the brain but in fat tissues--and neuropeptide Y, identified in 1983. Yanagisawa speculates that a lack of leptin, which supresses hunger, may, in fact, prompt the brain to produce orexins, which cause hunger. Manipulating this feedback system could also help patients with adult-onset diabetes mellitus.

Representatives of pharmaceutical firms are now gathering outside Yanagisawa's lab door. But whether orexins lead to improved treatments for eating disorders or not, the discovery is an impressive piece of scientific work. Other molecular biologists note that it took 10 years for researchers to learn as many details about neuropeptide Y. And in an accompanying article in Cell, Jeffrey B. Flier of the Beth Israel Deaconess Medical Center in Boston hailed the study as nothing less than "a technical tour de force."

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