Enzyme Study : Lab Mice Give Their All to Fight Obesity

Times Staff Writer

With what may have been a sudden premonition of its fate, the laboratory mouse bit Stanley K. Wong savagely on the finger.

Wong screamed, then quickly recovered his professional demeanor. "The lean ones are always more vicious," he said.

In truth, the mice in Wong's laboratory have reason to be ill-tempered. All have been bred either fat or skinny, and recently journeyed via the postal system from Massachusetts to the College of Osteopathic Medicine of the Pacific here. Worse, their tissues are destined for a centrifugal sorting machine.

But their sacrifices may one day allow human beings to lose weight by speeding up the body's metabolism.

Wong believes that a genetic defect in the cells, and not overeating, is responsible for obesity. His research, he hopes, will lead to the development of drugs or hormones that will make overweight bodies burn energy more quickly.

"The ultimate thing in this research is to develop a drug that can change obese mice into lean ones," he said.

Before he can do that, Wong must prove that a link exists between excessive weight and the internal workings of the cell. The key, he says, is an enzyme that helps govern the rate at which the cell breaks down energy.

And while scientists have been searching for this link in human blood cells for nearly a decade, Wong says many experiments forbidden in human patients can be conducted freely on rodents.

This does not bode well for the mice.

There will be much dissection, injection, probing and biting back in the years to come. If they are lucky, the last mice involved in the research project will waddle into the lab and emerge again as trim as the people whose pictures are displayed on the "after" side of weight-reduction advertisements.

Wong, 33, received a $49,600 grant recently from the American Diabetes Assn. to perform his experiments. As an assistant professor at the college, he has done similar research on the cell's relationship to diabetes and hypertension, and says a better understanding of both these maladies may stem from his work.

"The reason I'm interested in obesity is because I'm also interested in the role of the enzyme in diseases," Wong said.

His fascination with metabolism began when he was working toward his doctorate in pharmacology at the University of Wisconsin, where he said he first learned of attempts in 1978 to link obesity to metabolism.

Results of experiments with rodents published that year by George A. Bray of the UCLA Medical Center, Wong said, were fascinating but did not prove conclusively that obesity is related to enzymes.

Studies of obesity and human blood cells by scientists at the University of California, San Diego, and Harvard since 1980 tend to support the hypothesis, Wong said, but further research is needed.

Although Wong was uncertain of his future on graduation day in 1979, he said the development of Bray's theory attracted him to the field.

"The hypothesis is that obesity is a clinical disorder, an imbalance between the caloric intake and expenditure of the body," Wong said. "It is the patient's inability to use up energy. If the enzyme is impaired, it does not break down energy as fast. It's like a car engine; instead of running at 50 m.p.h., it only runs at 20 m.p.h."

Similar defects in the cell, Wong said, can lead to the accumulation of calcium in blood vessels, causing them to be rigid, and in turn causing hypertension.

While obese humans and animals have a tendency to overeat, Wong

said there is no evidence to suggest that the reasons for overeating are genetic. "The current thinking is that overeating is behavioral," he said. "In laboratory tests, even though they were given equal diets, obese rats gained more weight than lean rats," he said.

The grant is for a two-year period. Wong said he hopes initial success will bring more funding and allow the project to continue up to five years.

But even if Wong finds the cure for obesity, he said it may be 20 to 30 years before drug manufacturing firms are able to develop a version that the Food and Drug Administration will consider safe.

"There's a lot of red tape in the FDA," Wong said.

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