Single enzyme to blame for potbellies:

Research in mice could lead to belt-tightening pill, stave off obesity-related ills

December 6, 2001 - A single enzyme, not just a lack of sit-ups, may be to blame for some potbellies, a new study in mice suggests. The finding could eventually pave the way for a pill that deflates spare tires and heads off the risk of diabetes and other obesity-linked diseases, experts say.

People who pack on excess pounds around their waists face a much higher risk of developing heart disease, diabetes and other maladies than people who store fat in other areas, such as thighs or hips, studies show. So a team of researchers lead by Dr. Jeffrey Flier, an endocrinologist at Beth Israel Deaconess Medical Center in Boston, set out to explain the so-called "apple-shaped body" syndrome. What they found was that a single enzyme in fat cells that raises levels of cortisol - the "fight or flight" stress hormone - triggers fat accumulation around the belly and its associated ill effects.

We discovered that one particular enzyme seems to be extremely important for regulating the amount of fat an animal has in its abdominal area," said Flier, also a professor of medicine at Harvard Medical School.

The researchers were drawn to the role of cortisol because patients with a rare illness known as Cushing syndrome - who have too much of the steroid hormone in their blood - develop severe obesity concentrated around their middles and become diabetic.

Since overweight people without Cushing syndrome typically don't have too much cortisol in their bloodstreams, Flier hypothesized that they may be producing high cortisol levels solely in their fat cells - possibly because the enzyme HSD-1, which makes cortisol from an inactive molecule, is overactive.

So Flier and his team genetically engineered a strain of mice to moderately overproduce the HSD-1 enzyme in their fat cells and compared them with normal mice. For the first nine weeks of life both groups of mice were fed low-fat diets and their weights were the same.

But as the mice entered adulthood, the engineered mice steadily ate more and grew fatter. By 15 weeks, they weighed 16 percent more and carried a much larger proportion of their body weight around their abdomens than normal mice.

The level of cortisol in their stomach fat tissue was 15 percent to 30 percent higher than in their non-engineered counterparts.

When the animals were fed a high-fat diet, the engineered mice also were significantly more prone to weight gain - they packed on 20 percent more weight than the normal mice.

Cortisol appears to increase appetite and cause fat cells in the belly to suck up fat from the bloodstream and store it there, Flier said.

The engineered mice also developed diabetes, high blood pressure and high cholesterol.

POSSIBLE NEW TREATMENT PATHWAY

This is an important piece in the puzzle to understanding different types of obesity and the link between obesity and diabetes," said Dr. Bob Farese, an endocrinologist who studies fat metabolism at the Gladstone Institute of Cardiovascular Disease at the University of California, San Francisco.

The [genetically modified] mice enabled the researchers to keep all things constant except for the enzyme. They just changed the enzyme, which produced wide-ranging effects - this implicates a direct causal agent," Farese said, adding that the enzyme offers a potential new pathway for treating obesity.

Attacking this enzyme may well be a valuable way to treat obesity and its related complications," Flier said. "A number of pharmaceutical companies are already interested in the compound."

But he said any human trials of a potential drug to block the enzyme are several years off.

By Julia Sommerfeld
MSNBC

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