Skip to comments.Stanford Scientists' Discovery of Hormone Offers Hope For Obesity Drug
Posted on 11/15/2005 6:44:03 AM PST by snarks_when_bored
STANFORD, Calif. — 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 drugmakers alike.
The research was sponsored by Johnson & Johnson Pharmaceutical Research & Development, LLC, which has certain license rights to the discovery.
Researchers at the Stanford University 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, PhD, an endocrinologist and professor of obstetrics and gynecology. Jian V. Zhang, PhD, a postdoctoral scholar in Hsueh's laboratory, is the lead author.
Drugmakers 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. And 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 Greg Barsh, MD, PhD, 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," said Hsueh.
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," said Hsueh.
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," said Hsueh.
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," said Hsueh. 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.
I'll leave it for others to ponder the significance of the fact that the discoverers of obestatin are of East Asian extraction (though I'll venture to guess that they were neither born nor educated in Dover, PA, or Kansas).
Pinging it here, Boss...
I kind of like the idea of 'take a pill, chill, lose weight'.
Junior, archival ping.
Y'all calling me fat? LOL!
Y'all calling me fat? LOL!
Understood. I thought this piece interesting because it highlights the way in which the scientific principles of evolutionary theory guided the inquiry, resulting in the discovery of a hitherto-unknown hormone.
True. But if you scan the literature, stuff like this happens almost every day (but not, of course, for the creation science folks). I want to ping the list for biggies.
Most people gain about 2 pounds a year after age 30. By age 70 this makes you 80 pounds overweight.
Gaining two pounds a year is equivalent to eating an unnecessary piece of dry toast every day.
The normal body has an amazing fat thermostat, but it's biased towards slow weight gain -- as it should be in times and places where food is scarce, or the supply unreliable.
If there is a way to turn down that thermostat by one piece of dry toast a day without using addictive drugs, I'm in line for it.
Even some of these hormones don't work if used. For example, a lot of fat people are leptin resistant because of the constant high circulating level of leptin in their bodies. You'd have to cut their food intake and let them desensitize to it before it would ever have an effect.
Uh, read this:
We just don't know enough yet to make a pill that will work. That will change, though. We're just getting started.
Exercise. When you eat over maintenance, do you want your body to say "I need to use these excess calories to build muscle, mitochondria and red blood cells.", or do you want it say "I have no need for additional performance, let's store some fat!". :-)
Likewise when you undereat do you want your body draw calories from muscle or fat?
A simple 30 minute weightlifting routine using full body compound exercises done 2-3x a week will keep your body in a state of near continual remodeling. Tack on 30 minutes of hard aerobic exercise on the end and you're helping insulin resistance and your cardiovascular health.
3 hours a week is only 2.5% of your waking hours every week, you just have to decide if being healthy and strong is worth that small investment of time. For me it is, because it makes the other 97.5% much more enjoyable.
My guess is that the hormones that keep the metabolism high begin to decline, so it takes less food to maintain the same weight. Exercise is certainly helpful (I say necessary), but it also tends to increase my appetite. So while lots of exercise and calorie counting will get the weight off, it's not enjoyable and requires massive discipline and sacrifice as well as a total change in eating habits.
I'd be interested in specifically what 'principles' these researchers used and how they used them to make this discovery. Anyone have a link to something with more detail?
" Most people gain about 2 pounds a year after age 30. By age 70 this makes you 80 pounds overweight."
They usually lose about 1/2 a pound of muscle a year too. Muscle requires a large amount of calories to maintain; the *slowdown* in metabolism can largely be accounted for by the loss of lean muscle. Not for everybody of course, but probably for most people.
The moral of this story? Maintain your muscle and your metabolism will stay about even.
One of these days I will actually live up to that moral too. :)
You can fight it all you want, but it's a losing battle. You might put it off ten years or so.
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