The prevailing view about what makes visceral fat special has been its location, according to C. Ronald Kahn, president and director of the Joslin Diabetes Center. As Scherer points out, "It is in a privileged position with respect to the liver," into which the fat dumps a rich concentration of chemicals collected from the abdominal cavity. It wraps around the intestines and thus has "first dibs" at nutrients, Scherer adds.
But is there something distinctive about the fat itself? "Maybe the fat in different depots is intrinsically, developmentally different," Kahn says. He was encouraged in his thinking by, among other things, the question he repeatedly heard at cocktail parties: "You study fat, Dr. Kahn. Tell me, why is it that when I gain weight it goes right to my hips?" He pondered it over his canapés. "Why should this be if all fat cells are equal? Why do different families gain in different ways?"
Kahn started with mice. He and a colleague took samples of both visceral and subcutaneous fat from the mice and, using gene chips, identified the genes in the fat cells as well as in precursor fat cells. Among the 20,000 mouse genes, the researchers found 200 that were different in the two fat depots. Twelve of those were genes that control fundamental aspects of development, which is "twice what you'd expect," Kahn says. Some of the 12 genes were expressed much more in one kind of fat than in the other, in many cases at rates 100 times higher.
At Kahn's request, a colleague in Germany, Matthais Blüher of the University of Leipzig, looked at 10 of the same genes in samples of visceral and subcutaneous fat he had taken from humans (a third of the subjects were lean, a third overweight, and a third obese). He found up to 1,000-fold differences in the levels of gene expression. "Some genes were turned way on in subcutaneous fat," Kahn reports, "and others were turned way on in visceral fat." Three of the genes seemed to be related to overall obesity. When the scientists looked at the level of the genes' expression, they could correctly identify the body mass of the person the fat came from. "It is pretty clear," Kahn sums up, "that both obesity and body shape are to a large extent genetically programmed."
James Kirkland of Boston University Medical Center would agree. From his own work, he concludes that fat distribution has an even stronger genetic basis than obesity, with the former 70 percent attributable to hereditary factors compared with 40 to 50 percent for the latter. When Kirkland took progenitor fat cells from human fats—subcutaneous, omental, and mesenteric—and cultured them, they retained their distinctive characteristics even after 40 population doublings. "They seemed to retain a memory of the fat depot they came from," he says.
You don't need gene chips to see genetic influence in human body shape: think of Hottentot women with their steatopygous buttocks or "the elderly Indian gentleman with skinny legs and arms and no butt but this gut," as Scherer puts it. Studies show Southeast Asians are particularly prone to visceral obesity, which may help explain why India has such a high rate of type 2 diabetes—more than 12 percent of the population is affected, nearly twice as high as the U.S. incidence. The Indian gentleman also illustrates that not everyone who is generally lean is healthy, and not everyone who is obese is at risk. There ought to be a new definition of obesity, Hamdy proposes, "one based on the location of fat rather than on its volume."
Recent studies show that the health problems associated with visceral fat are wide-ranging. Over the past two decades, research scientist Rachel Whitmer at the Kaiser Permanente Division of Research in Oakland, California, has tracked over 6,000 members of Kaiser starting when they were age 40 to 45 in an effort to learn if there is a connection between central obesity and dementia. She has found an alarming link: Subjects who had a healthy weight at midlife but were, nevertheless, in the top 20 percent of the study population in central obesity (the amount of fat around the middle) were 65 percent more likely to develop dementia than those in the bottom 20 percent. "Measures of central obesity are more important than total weight," she concludes. What was responsible for the mental decline, Whitmer speculates, was a "lifetime exposure to metabolic dysregulation."
Other studies show that visceral obesity raises a person's risk of developing colon cancer, perhaps because it increases circulating levels of hormones that affect cell growth. Also elevated: gallstones (because of insulin resistance in the liver?), gastrointestinal disease (increased immune activity?), terminal cirrhosis (insulin resistance and fatty liver?), breast cancer, ovarian cystic disease, and sleep apnea. Després notes that there's a correlation between waist and neck circumference, and people who suffer from sleep apnea may have excess fat inside their necks.
What can be done to minimize fat and the trouble it causes? Lose weight; even modest losses reduce health risks, and visceral fat stores seem to go first. (Subcutaneous fat is actually harder to get rid of.) A second piece of advice: Do not eat trans fats. In a recent study at Wake Forest University in Winston-Salem, North Carolina, 42 male vervet monkeys were fed the same number of calories but in different oils—either as ordinary monounsaturated fat or as trans-monounsaturated fat—every day for six years. Only the trans fat, which is modified chemically to stiffen the fat to prolong its shelf life, had a negative health impact. The animals that ate trans fat not only packed weight in their bellies but also developed signs of insulin resistance. "It looked as if the metabolic syndrome was developing," says Lawrence Rudel, a biochemist at Wake Forest and the director of the study.
Another fat fighter is exercise. Chris Slentz, senior research scientist at Duke University Medical Center, found during an eight-month study at Duke that men and women in their early fifties who took a brisk half-hour walk six times a week saw no increase in their visceral fat stores (and those who walked or jogged more reduced those stores), while controls, who ate the same amount but didn't exercise, had an 8.6 percent increase in their visceral fat.
Reducing stress also helps. Studies in mice have shown that excess glucocorticoids—stress-related hormones—can produce visceral obesity and diabetes. Surgically excising part of a person's visceral fat, as Edward Mun did for Frank Garofolo, helped four of the other five obese patients he tried it on; their insulin sensitivity, blood sugar, and cholesterol showed modest improvement. Yet "it's not going to be an established practice," Mun insists. "We already have very good gastric bypass and banding procedures, which cause weight loss and are well established and safe—and don't take two hours." (And forget about liposuction, since it leaves visceral fat in place and could even augment it.)
Kahn thinks that scientists may eventually be able to redistribute fat by turning off developmental genes. Or they may be able to insert subcutaneous fat—which, in addition to serving as an energy bucket, "may be making some beneficial substance"—into depots of visceral fat. Or they may use hormones to convert visceral to brown fat, a type of fat (most often found in infants) that burns calories rather than stores them.
Meanwhile, researchers are looking for drug strategies. In the lab of Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine, Francine Einstein (not a descendant) has given an experimental drug to 30 rats while shining a light on their visceral fat. Within three weeks, the animals had lost 40 to 60 percent of the fat. The goal is to do the same for humans someday and thus improve their insulin sensitivity. If that approach succeeds, Garofolo may finally share in the lab rats' good fortune.