Research tries to make fat more fit

Facing a national epidemic of obesity, Medical College of Georgia researchers are looking for ways to prevent the hefty from developing heart disease and diabetes.


This "fat but fit" idea is exemplified in a specially bred mouse model that packs on weight without developing the insulin resistance that can lead to diabetes and heart problems.

Researchers David W. Stepp and David Fulton have a $2.5 million grant from the National Institutes of Health to study the link between obesity and cardiovascular disease through peripheral insulin resistance, an inability to use the normal muscle system to clear insulin.

"One of the problems in obesity is you become progressively insensitive to insulin," said Dr. Stepp, a co-director of MCG's new Diabetes and Obesity Discovery Institute. That can lead to type II diabetes and, the researchers believe, can contribute to cardiovascular problems.

To discover how this happens, the team created a "knockout mouse" that lacked the hormone leptin so the mice grew very fat, about three times the weight of normal mice, Dr. Stepp said. But these mice were also missing a gene called protein tyrosine phosphatase 1B, or PTP1B, which normally acts to desensitize the body to insulin. Now that those obese mice were sensitive to insulin, they did not develop the same metabolic and cardiovascular problems of other obese mice.

"It should be fat but fit," Dr. Stepp said.

The researchers are still trying to detail how it is that peripheral insulin resistance can lead to cardiovascular damage. It appears to be a high swing of glucose levels in the blood, which leads to the appearance of a receptor that is suspected in a number of diseases, from Alzheimer's to diabetes to hypertension. This, in turn, can create inflammatory signals and oxidative stress, which create their own problems.

The idea is to figure out why obesity is causing these problems, because it is probably not just fat, Dr. Fulton said.

"A certain level of adiposity (fatness) is healthy, I'm sure people will be happy to hear," he said. A large number of people are obese -- 72 million, according to the Centers for Disease Control and Prevention -- and the vast majority of people who try to lose weight fail, Dr. Stepp said.

So the researchers are looking for genes to "break the link" between obesity and these other health problems, he said. Unfortunately, "all of the drugs targeting PTP1B are busts," he said, but following the path of how obesity can lead to the other diseases could land them in the right place. "I think a lot of the problem with targeting some of these drugs is basically we need a better diagnostic strategy," he said, which could include PTP1B. "We need to better clarify what the players are in obesity-related cardiovascular metabolic disease. And then I think we'll be able to use genetic screening to either design drugs or target existing drugs more effectively."

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