OBESITY RESEARCH:Pot-Bellied Mice Point to Obesity Enzyme Trisha Gura People who carry excess fat around their waists are known to be more prone to obesity-related maladies than their equally overweight counterparts who pack weight around their hips, but no one has been able to explain the connection. Now on page 2166, researchers suggest a reason for the disease-body type relationship and a possible new target for treatment. The culprit is an obscure enzyme that works to recycle a steroid stress hormone called cortisol. OBESITY RESEARCH:Pot-Bellied Mice Point to Obesity Enzyme Trisha Gura* Words linking fruit and the human anatomy have long sweetened sonnets and love letters. But lately the term "apple-shaped" has gained renown on the pages of medical texts. People who carry excess fat around their waists--the so-called apple-shaped body type--are more prone to obesity-related maladies than their equally overweight but pear- shaped counterparts, who pack weight around their hips. Physicians have observed the connection for decades, but no one could explain it, let alone search for a therapy to right the scales. Now on page 2166, researchers at Beth Israel Deaconess Medical Center in Boston suggest a reason for the disease-body type relationship, and a possible new target for treatment. The culprit is an obscure enzyme that works to recycle a steroid stress hormone called cortisol. Through delicate genetic engineering, endocrinologist Jeffrey Flier and his colleagues overexpressed the gene for this enzyme solely in the fat of mice. These rodents look and act a lot like overweight apple-shaped people: They eat more than normal mice and gain fat disproportionately around their middles. As adulthood sets in, the animals develop the early biochemical symptoms of heart disease and diabetes. Blocking the enzyme in people, the researchers suggest, might thwart obesity- related illnesses. Belt loosener. Activating an enzyme in fat gives mice a syndrome seen in apple-shaped people. CREDIT: PHILIP HARVEY/CORBIS "This was really the first proof that manipulating steroid conversion in fat alone is enough to lead to all these abnormalities," says endocrinologist Stephen O'Rahilly of Addenbrooke's Hospital in Cambridge, U.K., who studies the genetics of obesity and diabetes. "I wish I'd done the experiment myself." Inspiration for the study came indirectly from a rare illness called Cushing syndrome. Its sufferers have too much cortisol coursing through their bloodstreams and become diabetic and severely obese. For decades, endocrinologists hypothesized that common forms of obesity may represent very mild cases of Cushing syndrome. If so, most obese people should have higher than normal blood levels of cortisol--but researchers found that they don't and discounted the hypothesis. The theory was resurrected by Paul Stewart of the University of Birmingham in Edgbaston, U.K., whose group found that people have pockets of high cortisol activity. The team compared stress hormone production in two types of fat in 16 patients undergoing surgery, most of whom were of normal weight. One sample came from underneath the skin, the other from adipose tissue in the abdomen. In the belly fat, the researchers found higher activity of an enzyme called 11b hydroxysteroid dehydrogenase type 1 (11b HSD-1), which regenerates active cortisol from its inactive form, cortisone. Flier read a 1997 paper in The Lancet on the research and thought, "If we could make a mouse that overexpresses the enzyme only in fat, we could ask the question, 'Will that mouse get the apple-shaped body type and all its ill effects?' " he recalls. Visiting scientist Hiroaki Masuzaki engineered the mice; he linked a rat 11b HSD-1 gene to a promoter that turns on only in fat. The mice had 2.4 times more enzyme activity in their belly fat than did normal mice. Stress hormone levels in stomach fat tissue rose by 15% to 30%, but, as in most obese humans, bloodstream levels of the hormone were normal. As adulthood set in, the transgenic mice ate more, got fatter than normal mice, and carried the fat in their abdomens. Even when fed low-fat diets, the transgenics carried a spare tire that accounted for 37.9% of their total body fat compared with 27.5% in normal mice. The mice showed the hallmarks of early diabetes and hypertension: insulin resistance, renegade blood glucose levels, and other biochemical abnormalities. And a high-fat diet accelerated the pot-bellied rodents' downward spiral. "It is really the whole picture of what we refer to as the metabolic syndrome," says Flier, citing a term now in vogue in endocrinology circles to describe the growing population of obese people at risk for diabetes and heart disease. But O'Rahilly points out that no one can yet pin down 11b HSD-1 as the cause of the millions of cases of diabetes and heart disease. "You have to find out whether the level of metabolic disturbance in people correlates with the activity of this enzyme," O'Rahilly says. Meanwhile, two recent clinical observations support the team's results: In April, Joel Berger's group at Merck Research Laboratories in Rahway, New Jersey, showed that a class of antidiabetic drugs now on the market suppresses 11b HSD-1 levels in fat cells. And Eva Rask of Umeå University Hospital in Sweden and Brian Walker of the University of Edinburgh, U.K., report that obese men express higher levels of 11b HSD-1 activity in fat tissue than do lean males, which begins to address O'Rahilly's concerns. Flier and O'Rahilly both say they are aware of drug companies that have in hand, or are scrambling to come up with, potent inhibitors of the enzyme. Such compounds might be used to treat obesity by altering stress hormone levels in belly fat. "We have wanted to know for some time what properties of fat inside the abdomen make it different from fat outside the abdomen," says O'Rahilly. "If this enzyme explains it, that would be interesting indeed." Trisha Gura is a science writer in Cleveland, Ohio. Gura, Trisha, OBESITY RESEARCH: Pot-Bellied Mice Point to Obesity Enzyme. , Science, 12-07-2001.