Single enzyme may be linked to obesity

December 06, 2001

BOSTON - The increased activity of a single enzyme in fat cells may be a common cause of obesity and obesity-linked diseases, including diabetes, according to an animal study conducted by researchers at Beth Israel Deaconess Medical Center and the University of Edinburgh and published in the Dec. 7 issue of Science. The findings could eventually pave the way for future drug development to curb visceral obesity - the "beer belly" fat concentrated in the abdomen.

"Hundreds of studies have led to the conclusion that any fat can be problematic, but it's much, much more dangerous when it's accumulated in the abdomen," notes lead author Jeffrey S. Flier, M.D., an endocrinologist at Beth Israel Deaconess Medical Center and the George C. Reisman Professor of Medicine at Harvard Medical School. "Pound for pound, intra-abdominal fat is much more likely to cause diabetes, heart disease and other diseases that make up the metabolic syndrome."

To identify the molecular mechanism behind the accumulation of the excess abdominal fat, Flier and his colleagues looked at the role of the glucocorticoid hormone cortisol, the "fight or flight" hormone that helps people survive stressful situations. Observations of patients with the endocrine disorder Cushing's syndrome - who have too much cortisol in their blood - had shown that they develop increased intra-abdominal fat as well as other metabolic symptoms. This led Flier to hypothesize that obese patients - who don't typically have increased blood cortisol levels - may be producing increased amounts of cortisol in their fat cells.

To test this hypothesis, Flier and his colleagues studied the enzyme 11beta hydroxysteroid dehydrogenase type 1 (11 beta HSD-1), which has the unique ability to produce cortisol in cells that are not normally associated with cortisol production. This enzyme is known to be present in fat cells.

The researchers created a group of transgenic (Tg) mice that overproduce 11 beta HSD-1 in roughly the same quantities previously found in the fatty tissue of obese humans. As predicted, these mice had increased levels of cortisol in their fat, but not in their blood. The Tg mice were then compared with a group of non-Tg mice. For the first nine weeks of life both groups of mice were fed low-fat diets, and their body weights were indistinguishable. But, after nine weeks, the Tg mice steadily gained weight, and by 15 weeks of age, weighed 16 percent more than the non-Tg mice. The Tg mice were also more sensitive to weight gain when fed a high-fat diet. An external examination of the mice showed prominent weight gain in the abdominal areas of the Tg mice.

Further tests using X-ray absorptiometry to measure fat in the whole body and in the abdominal region showed that fat accumulation in the abdominal region of non-Tg mice on high-fat diets was comparable to that of Tg mice on low-fat diets. The ratio was further exaggerated when Tg mice were fed high-fat diets.

"We were surprised to find that it took only a modest increase in this enzyme to cause the mice to become viscerally obese. The animals also developed diabetes, became resistant to insulin, developed high blood lipids and actually ate more. We now also know that the mice became hypertensive," says Flier.

"This study tells us that increasing this single enzyme in fat cells results in an unexpectedly major impact," he adds. Coupled with findings from the University of Edinburgh showing a correlation between increased enzyme activity in fat tissue and obesity in human subjects, the findings strongly suggest that the 11 beta HSD-1 enzyme is an exciting pharmaceutical target for the treatment of visceral obesity.

"Obesity is a massive problem in our population," says Flier, who has been studying the molecular mechanisms of obesity for the past decade. "It's linked to a huge burden of disease - hypertension, coronary disease, atherosclerosis, cancers, reproductive disorders, diabetes. In fact, an estimated 80 percent of diabetes cases would not exist in the absence of obesity. If we could attack obesity, not only would people feel better, it would also improve all of these other disease states."
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Study co-authors include Hiroaki Masuzaki, M.D. and Hiroshi Shinyama, M.D., of Beth Israel Deaconess Medical Center, and Janice Paterson, Nicholas M. Morton, M.D., John J. Mullins, M.D., and Jonathan R. Seckl, M.D., of the University of Edinburgh, Scotland.

This research was funded by the National Institutes of Health (NIH) and Eli Lilly. Beth Israel Deaconess Medical Center is a major patient care, research and teaching affiliate of Harvard Medical School and a founding member of CareGroup Healthcare System. Beth Israel Deaconess is the fourth largest recipient of National Institutes of Health Research funding among independent U.S. teaching hospitals.

Beth Israel Deaconess Medical Center

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