People who carry excess fat around their waists--the so-called apple-shaped body type--are more prone to obesity-related maladies than their pear-shaped counterparts, who pack weight around their hips. Now, a new study suggests a reason for this decades-old observation--and a possible target for treatment. The culprit, according to a study in the 7 December issue of Science, is an obscure enzyme that works to recycle a steroid stress hormone called cortisol.
Endocrinologists have long speculated that obesity might have to do with an excess of cortisol. But the theory was discounted by the fact that most obese people don't have higher than normal blood levels of the hormone. In 1997, however, scientists discovered that there are pockets of high cortisol activity: In human belly fat, they found higher activity of an enzyme called 11b hydroxysteroid dehydrogenase type 1 (11b HSD-1), which regenerates active cortisol from its inactive form, cortisone.
Inspired by that finding, endocrinologist Jeffrey Flier and his colleagues from Beth Israel Deaconess Medical Center in Boston genetically engineered mice to overexpress the enzyme solely in their fat. Stress hormone levels in that tissue rose by 15% to 30%, but bloodstream levels were normal. As adults, they ate more, got fatter than normal mice, and carried the fat in a spare tire around their abdomen. The mice also showed the hallmarks of early diabetes and hypertension. And a high-fat diet accelerated the downward spiral of the pot-bellied rodents.
"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."
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.
Flier and O'Rahilly both say they are aware of drug companies that have in hand, or are scrambling to come up with, other potent inhibitors of the enzyme. Such compounds might be used to treat obesity by altering stress hormone levels in belly fat.