Hormone finding offers new hope for obesity drug
BY ROSANNE SPECTOR
When the appetite-enhancing hormone ghrelin was discovered a few years ago, researchers thought they had found the last of the major genes that regulate weight.
They were wrong.
Introducing obestatin, a newly discovered hormone that suppresses appetite.
The finding, published in the Nov. 11 issue of Science, offers a key to researchers developing treatments for obesity. In a nation that desperately needs to slim down—the U.S. Centers for Disease Control and Prevention estimates 65 percent of Americans over the age of 20 are either overweight or obese—obestatin is likely to generate interest from scientists and drug-makers alike.
The research was sponsored by Johnson & Johnson Pharmaceutical Research & Development LLC, which has certain license rights to the discovery.
Researchers at the School of Medicine uncovered obestatin by using the principles of evolution to pick clues from data held in the Human Genome Project, as well as the genome sequencing projects for many other organisms, among them yeast, fruit flies and mice.
"Darwin led us to this new hormone," said senior author Aaron Hsueh, an endocrinologist and professor of obstetrics and gynecology. Jian V. Zhang, a postdoctoral scholar in Hsueh's laboratory, is the lead author.
Drug-makers could use new insights into weight regulation. The discovery of the appetite-suppressing hormone leptin in 1994 and the appetite-boosting hormone ghrelin in 1999 offered high hopes of more effective drugs. In the past few years, the influence of melanocortin hormones on regulating leptin has become clearer. But these insights have yet to yield a treatment for obesity.
"There are several known pathways that regulate body weight: ghrelin, leptin and melanocortin," explained Dr. Greg Barsh, a Stanford professor of genetics who studies melanocortin and was not involved in the obestatin project. "This work is notable because it represents a completely new pathway."
The new finding could clear up some confusion over how appetite-regulation hormones work. Since the ghrelin protein increases appetite, scientists had expected that animal experiments deleting the protein's gene would turn appetite off.
But when they tested this theory, they found that deleting the gene linked to ghrelin had almost no effect on growth or appetite. The likely reason? Hsueh's finding shows that deleting the gene for ghrelin also takes out obestatin.
It's rare for more than one protein to come from a single gene sequence. What makes this case even more unusual is that two proteins from the same sequence have such opposite effects: Obestatin behaves in some ways as the "anti-ghrelin."
"That was a big surprise," Hsueh said.
The identification of obestatin occurred as part of the researchers' study of a specific category of hormones—relatively small protein molecules called peptide hormones. These are of particular interest to drug developers because they bind to a type of receptor molecule known as a G-protein-coupled receptor, or GPCR. "These receptors represent targets for almost 50 percent of the drugs in the market," Hsueh said.
GPCRs activated by small-peptide hormones are especially promising. That's because small peptides, unlike larger ones, tend to be easier to synthesize and deliver to patients.
So why does Darwin's theory deserve some credit? Hsueh explained that before he and his colleagues started the project, they used the genome projects' information to create a database of GPCRs that grouped them according to their evolutionary relatedness.
From the 300 GPCRs found in the human genome, the researchers selected about 100 that had no known hormone partner. They then chose those 30 that seemed most likely to interact with a peptide hormone, basing this choice on evolutionary analyses.
"These sequences stood out because they each have evolutionarily close 'sister genes' known to bind peptide hormones," Hsueh said.
Next, they focused on identifying the unknown hormone partners. Darwin again lent a hand. Hsueh and colleagues narrowed the search by focusing on sequences that have been conserved during hundreds of millions of years of evolution—in organisms as diverse as fish and humans—because these are likely to be of greatest biological importance. They zeroed in on several sequences, including the one known to make ghrelin, the appetite-enhancing hormone. That sequence appears in humans and at least 10 other mammals.
Analysis of the ghrelin pre-hormone sequence revealed an additional protein tacked on at the end. The researchers promptly set out to synthesize and learn more about this protein, which they later named obestatin.
"There are no set rules for identifying bioactivity but most of the known peptide hormones are brain/gut hormones," Hsueh said. So the researchers set out to discover whether obestatin is present in rat stomach tissues and brain. It is.
Encouraged, they investigated obestatin's effects on laboratory animals. They found that injecting it into rats' abdomens and brains decreased food intake and suppressed weight gain. Rats given obestatin injections ate about half as much as those given no obestatin. Obestatin treatment also slowed the movement of digested food from the stomach into the intestines.
All that remained for the researchers to do was to match this newly discovered hormone to the right receptor.
Once again, evolutionary conservation made their work a little easier. Instead of testing each of the 30 previously identified GPCRs, they started with what the evolutionary record told them was the most likely candidate. Their hunch was that the receptor for obestatin would be closely related to the receptor for ghrelin. A whirl through their database showed them that GPR39 was closely related to the receptor for ghrelin.
Sure enough, later experiments showed them that GPR39 was in fact a receptor for ghrelin's antithesis, obestatin.