Dallas study could help in obesity treatments

Scientists generate rats able to use hormone to burn fat cells' fat stores

07:01 AM CST on Tuesday, February 10, 2004

By SUE GOETINCK AMBROSE / The Dallas Morning News

http://www.dallasnews.com/sharedcon...cells.ca1a.html

Dallas scientists have created what dieters dream of – a new type of body cell that burns fat instead of storing it.

If the research, done with rats, also applies to people, it may open the door for new obesity treatments.

Researchers from the University of Texas Southwestern Medical Center at Dallas generated rats that produce high levels of a hormone called leptin. Normally, the hormone signals body cells – with the exception of fat cells – to burn fat rather than store it.

But in the rats, the hormone caused the fat cells to turn into tiny furnaces that swiftly burned up their own fat stores. If doctors could pull the same trick in people, weight loss could be dramatic.

"Obesity would theoretically be impossible," said Dr. Roger Unger, the scientist who led the study. "You'd be in a vicious, futile cycle, wasting all the extra fat."

The new study was released Monday and will be published next week in the Proceedings of the National Academy of Sciences.

The hormone leptin made headlines more than eight years ago when scientists found that injecting it into obese mice caused rapid weight loss. But similar injections into obese people didn't have the same effect, showing that the vast majority of obese people are resistant to the hormone.

Famine defense

Nevertheless, scientists have continued to study the hormone to better understand how the body deals with excess calories in the diet. Now scientists understand that leptin is part of the body's defense against famine, a system that has without a doubt carried mankind's ancestors through millions of years of evolution.

Leptin is produced by fat cells that are filling with fat. The hormone travels through the bloodstream to other tissues, telling them to burn their fat. That makes sense, Dr. Unger said, because fat hampers the function of most body tissues.

Fat cells, on the other hand, are uniquely specialized for storing fat. By producing leptin, fat cells stake the body's claim on fat storage, ensuring that fat gets stored nowhere else. The fat cells simply ignore leptin's commands to burn fat. In this way, the body can fatten up in prosperous times, bracing for future famines.

In the new study, the UT Southwestern scientists injected rats with a virus carrying the gene for the leptin hormone. A week after the injection, leptin levels were 75 times higher than normal. By two weeks, leptin levels were still 10 times higher than normal. Body weight dropped 25 percent.

When the researchers examined the rats' fat cells under the microscope, there had been a dramatic change. Fat droplets had shrunk, and levels of mitochondria – tiny cellular compartments that convert fuel to energy – had soared. The cells appeared to have been reinvented to burn fat.

"It's a little amazing, isn't it, that you can make cells that evolved for millions of years to store fat do just the opposite?" Dr. Unger said.

Unanswered questions

Whether the same transformation would work in people remains to be seen, Dr. Unger said. First, using a virus-gene combination to deliver leptin wouldn't be safe in people, he said. Scientists would have to find another way to raise leptin levels.

Second, Dr. Unger said, the rats in the study were lean to begin with. The same technique doesn't work on obese rats because their fat cells are immune to leptin. So to apply the technique to obese people, researchers would have to find a way to eliminate that immunity to leptin. And, he said, it's not clear how long the modified fat cells would persist, and whether that would be safe.

"I think they would go back to their previous state in time, but I don't know that for sure," he said.

One of the scientists who discovered leptin, Dr. Rudolph Leibel, said the new work could be valuable in coming up with treatments for obesity.

"It's a nice demonstration of the fact that it is possible to convert the function of a fat storage cell into one that looks like it's a user of energy," said Dr. Leibel, a molecular geneticist at Columbia University in New York City.

However, he cautioned against too much excitement too soon. Humans may have a very different response to high leptin levels, he said. And he wondered whether all the weight loss could be attributed to fat burning by fat cells. It's possible, he said, that the liver is burning fat, too, something that in theory could impede the liver's normal function.

Last, he said, the animals must be experiencing a noticeable rise in body temperature if they are burning fat at such a rapid rate. That might not be safe for obese people who also have cardiac or lung problems. And it might not be much fun, either, he said.

"It could be one two-week-long, serious hot flash," he said.

Dr. Unger is director of the Touchstone Center for Diabetes Research at UT Southwestern and a physician at the Dallas Veterans Affairs Medical Center. Other UT Southwestern researchers on the paper were William Cook, May-yun Wang and Byung-Hyun Park. Mariella Ravazzola, Roberto Montesano and Lelio Orci of the University of Geneva Medical School in Switzerland also participated.

E-mail sgoetinck~dallasnews.com