Researchers have discovered a potential new target for appetite-altering drugs. In today's issue of Cell, a team led by Masashi Yanagisawa of the University of Texas Southwestern Medical Center in Dallas reports the discovery of two related peptides from the brains of rats that trigger eating.
Yanagisawa and his UT Southwestern colleagues, working with researchers at SmithKline Beecham Pharmaceuticals, discovered the peptides, which they call orexins (from the Greek word for appetite), during a routine search for peptides that activate so-called "orphan receptors." These are proteins whose amino acid sequences show the structural hallmarks of cell surface receptors but whose triggering molecules are as yet undiscovered. Out of this search came a pair of similar peptides that are made exclusively in the lateral hypothalamus, a part of the brain already known to help control appetite. "That was the obvious clue that they may be involved in feeding," says Yanagisawa.
To test that hypothesis, Yanagisawa's team injected the peptides into the brains of rats and found that they boosted the rats' appetite three- to sixfold. That was encouraging, but if the peptides really govern feeding, Yanagisawa reasoned, then the peptide levels in the brain should go up when the animals are hungry. The team deprived rats of food, says Yanagisawa, "and lo and behold [orexin] was up-regulated."
The orexins aren't the first peptides found to stimulate hunger, but because their receptors are known, researchers can start looking for drugs that either mimic or block their appetite-enhancing effects. And it's particularly good news that orexins are found only in the lateral hypothalamus, says appetite researcher Jeffrey Friedman of Rockefeller University in New York City. That suggests they are less likely to have lots of other functions and should make it easier to find drugs without troublesome side effects.