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Enzyme May Be Target for Future Obesity Drug

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Enzyme May Be Target for Future Obesity Drug


December 06, 2001 02:07 PM ET ?



By Maggie Fox, Health and Science Correspondent

WASHINGTON (Reuters) - A stress-related hormone may hold the key to the most dangerous type of obesity -- the so-called apple-shaped syndrome in which people get fat bellies and often diabetes, high blood pressure and heart disease, researchers said on Thursday.

They hope drugs can be designed that can help control the hormone and perhaps stave off the dangerous results of such obesity.

"This has the flavor of something that may be a mechanism that contributes importantly to typical obesity," said Dr. Jeffrey Flier of Harvard Medical School and Beth Israel Deaconess Medical Center in Boston, who led the study, published in Friday's issue of the journal Science.

More than 60 percent of Americans are overweight and more than a quarter are obese, meaning they have a high risk of health problems linked to their weight, according to the U.S Centers for Disease Control and Prevention (CDC).

Many studies have shown that it is often easy to tell who is most at risk by measuring waist circumference. This points to visceral fat, a build-up of fat inside the abdomen that is associated with the most dangerous effects of obesity.

People with a rare disease called Cushing's syndrome have too much abdominal fat as well as diabetes and high blood pressure, Flier said in a telephone interview, but the condition looks a lot like common obesity.

"This obvious fact caused many scientists and companies to wonder if it is possible that many patients with obesity have a mild form of Cushing's syndrome," he said. "That question has been asked over and over again."

The answer, however, is no. Cushing's is characterized by a high level of the stress hormone cortisol in the blood, and most obese people have normal levels.


Researchers studied the role of stress hormones and enzymes that affect them. One of particular interest was HSD-1. Cortisol is deactivated by several enzymes, but HSD-1 can reactivate it inside a cell.

Flier saw work by British researchers that suggested this could happen only in fat cells. "They raised the idea that you make too much (cortisol), but only in the abdominal fat cell itself," he said.

If this was happening, it would explain why some obese people have the extra abdominal fat without extra cortisol in their blood.

"The way I went about proving it with my colleagues was to create a genetic experiment and take a normal mouse, force the mouse to have more than normal level of this enzyme activity, but only in its fat cells," said Flier, who worked with Janice Paterson and colleagues at the University of Edinburgh. "We got exactly, even more than we bargained for."

The mice were fat and ate more than normal mice. "On top of that they developed diabetes, they developed high lipids in the blood (high cholesterol). They also developed high blood pressure," Flier said.

At the same time, British researchers reported they found the more fat people had in their bodies, the higher the level of the same enzyme, HSD-1, in their fat cells. The enzyme was working only in the fat cells, not in the rest of the body. It was like a localized version of Cushing's syndrome.

"We don't know why some people have more of this enzyme activity than others," Flier said, adding that he thought it could be a combination of genes, diet and exercise.

The immediate thought was that if a drug could stop the effects of the enzyme, people with the apple-shaped obesity problems could be helped.

Flier said several pharmaceutical companies, which he declined to name, are already working on such a drug.

He said another British team had genetically engineered mice that do not make any HSD-1 and they are healthy.

"You don't need the enzyme to live, which is good, and what is more, they reported ... when you put them on a high-fat diet, which normally makes an animal a little bit diabetic, those mice don't get diabetes."

Flier said he did not believe HSD-1 would turn out to be like another hormone linked with obesity -- leptin.

Obese rats lost weight when injected with leptin, raising hopes that leptin might be an easy diet pill. But obese humans were found to have above normal leptin levels and giving them additional leptin had little or no effect on their weight.

Flier says this one feels different. "Even though I can't prove it, I have a personal feeling this one will lead to something," he said.


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Maybe this one should be posted on the main board?  This is just incredible.  WOW.

You rock, Kristy :)

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I had it in my head to post it straight away as soon as I got back from my trip on Friday - I had to chuckle when not 5 minutes after I posted it, I saw the scan that MaryO had done of the clipping you had sent her! I was so really glad that someone else saw the article - Isn't it great! It almost seems that the research is starting to catch up with the disease....maybe in a few years there will be a non-invasive therapy available for hypercortisolism that works on the cellular level.


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