By David N. Leff

When buying a house, real estate agents tell you, there are three things to look for: location, location, location. The same maxim holds good for the location of fat buildup in the obese human body.

When the weight is situated in a man¿s abdomen, the protuberance is commonly called a ¿beer belly¿ or ¿spare tire.¿ But in recent years, observed endocrinologist Jeffrey Flier at Harvard-affiliated Beth Israel Deaconess Medical Center in Boston, medical literature and popular media have taken to describing that overweight male midriff as ¿apple-shaped.¿ Similarly, women with fat hips and thighs are called ¿pear-shaped.¿

These pomological contours, Flier said, ¿took over from the gynoid¿ vs. the android¿ pattern in medical practice, which stressed the fact that most women have the excess fat located on hips and thighs, whereas many men tend toward getting an abdominal pot belly.

¿It¿s now an established fact,¿ Flier pointed out, ¿that in addition to the issue of obesity and increased body fat generally being medically disadvantageous, where the fat is located is absolutely critical.¿ He explained: ¿Fat concentrated in the abdominal cavity is pound for pound many-fold more dangerous for all the complications of the metabolic syndrome. These range from diabetes, hypertension, coronary artery disease and atherosclerosis to cancer and reproductive disorders.¿

Flier is senior author of a paper in today¿s Science, dated Dec. 7, 2001, titled: ¿A transgenic model of visceral obesity and the metabolic syndrome.¿

¿The overall finding of this paper,¿ he told BioWorld Today, ¿is that a modest increase in the level of glucocorticoid hormone in fat, brought about by an enzyme called 11-beta HSD-1 [11b hydroxysteroid dehydrogenase type 1] is enough to drive a very potent obesity.¿

Evolution¿s Fight-Or-Flight¿ Gift Hormone

¿In mammals,¿ Flier noted, ¿the 11-beta HSD-1 enzyme is produced within a spectrum of different cell types, so it is present in a variety of tissues and organs. It¿s in the brain in certain cells. It¿s in fat, also in immune cells. Its function is to reactivate previously degraded or inactivated cortisol into its active form again. Human cortisol,¿ Flier explained, ¿is the fight-or-flight¿ hormone that enables an individual to survive stressful or dangerous situations. The way people understand the cortisol endocrine system is that it¿s produced through a whole series of steps in the adrenal glands, and gets released into the blood and its receptors all over the body¿s tissues and cells.

¿The subtext,¿ he added, ¿is that there are two enzymes, at least, that modify the cortisol inside the cells. One, HSD-2, inactivates the cortisol, and the other ¿ this 11-beta HSD-1 ¿ reactivates it. So why, physiologically, biologically, do you want to have an enzyme that does that? The canned answer is that it allows the body to get a higher level of control over what level of cortisol it wants in a given tissue at a given time. If you didn¿t have that system, what you¿ve got in the blood is what you¿ve got in all the different tissues.

¿The HSD-1 enzyme, it appears, is there to augment the level that is beyond what¿s in the blood,¿ Flier continued. ¿I can¿t give you a profound why¿ as to that. But one possibility is that it¿s part of the system that was developed to promote evolution¿s story of obesity vs. leanness as part of a survival mechanism to promote fat storage as a hedge against scarce food seasons.¿

Individuals who suffer from Cushing¿s syndrome ¿ too much cortisol in their blood ¿ develop increased abdominal fat, along with other metabolic symptoms. This led Flier to hypothesize that obese patients with normal cortisol blood levels may be producing greater amounts of the hormone in their visceral fat cells. To test this hypothesis, he and his co-authors studied the 11-beta HSD-1 enzyme, which has the ability to produce cortisol in fat cells.

They created a strain of transgenic mice that overproduce the enzyme in quantities similar to what¿s found in the fatty tissues of obese humans. As predicted, these animals turned out to have increased cortisol levels in their fat cells, but not in their blood.

For their first nine weeks of life, the team fed these mice and their normal littermates low-fat diets. Their body weights were utterly identical. But then, as adulthood kicked in, the transgenic mice steadily gained weight and by 15 weeks of age tipped the scales at 16 percent more than the normal control animals. A prominent part of that added weight was in their abdominal ¿apple-abs¿ location.

¿It took only a modest increase in this enzyme for the mice to become viscerally obese,¿ Flier recounted. ¿They also developed diabetes, insulin resistance, high blood lipids, hypertension ¿ and actually ate more.

¿The key finding of this experiment,¿ Flier said, ¿is that at the level of enzyme activity, the increase that we saw in these mice and the activity in their fat is, if anything, less than what has been reported in recent human studies ¿ in terms of obese people having higher levels of fat than of lean with this enzyme activity. So the mouse is not just some extraordinary experiment of nature, for which there doesn¿t seem to be any analogue. In humans that have increased activity in fat, they have even more.¿

The Most Compelling Therapeutic Target

¿We would now like to work with emerging compounds that inhibit the enzyme,¿ Flier indicated, ¿to examine its role in other animal models and human beings. That is, working toward developing therapeutic targets against visceral obesity. I believe this is one of the most compelling targets that I¿m aware of. Several pharmaceutical companies have selective inhibitors of the 11-beta HSD-1 enzyme already in their pipeline,¿ he noted. ¿We are not currently working with any of them.¿

Flier then cited another compelling target ¿ the human brain. ¿There has been a line of evidence by people in that area that this enzyme could play a role in preventing loss of cognitive function. A recent paper showed that a mouse with the enzyme¿s gene knocked out experienced much less cognitive decline with age. So inhibiting the 11-beta HSD-1 enzyme,¿ Flier concluded, ¿seems to be favorable also for some aspects of brain function.¿