Killer Fat

Not all fats are equal.

By Mariana Gosnell|Wednesday, February 28, 2007

"I wish I were a rat," Frank Garofolo, a 56-year-old investment banker in Boston, said recently. Garofolo has diabetes, as do his mother, father, and brother; his sister died of it. He had just been told about an experiment at the Albert Einstein College of Medicine in New York City in which a plump lab rat lost more than half its intra-abdominal fat when it was exposed to a drug-and-light therapy usually used to kill tumors. A couple of years earlier, Garofolo had submitted to experimental surgery himself at the Beth Israel Deaconess Medical Center in Boston, during which a surgeon pulled chunks of ivory-colored fat out through small openings in his belly. Although the loss of 4½ pounds of intra-abdominal fat allowed Garofolo to go from a tight size 44 belt to a loose one, it didn't have the effect he so fervently desired—boosting his insulin sensitivity and lessening the severity of his diabetes—leaving him desperate enough to envy a rat.

More than fat anywhere else in the body—even more than overall obesity—intra-abdominal, or visceral, fat is associated with pernicious health effects in humans. A major effect is reduced sensitivity to insulin, the hormone that helps glucose enter the body's cells. Biologists lump visceral obesity (having a large midsection) with a cluster of other more obvious physiological abnormalities—high triglycerides, high blood pressure, high fasting blood sugar, and low HDLs (high-density lipoproteins, the so-called good cholesterol)—under the umbrella term metabolic syndrome; people with this condition are at increased risk for cardiovascular disease and type 2 diabetes.

Studies have shown visceral obesity to be a risk factor on its own as well, a strong predictor of, among other things, heart attacks in young men, chronic heart failure in older people, high blood pressure in Japanese Americans, heart attacks in "well functioning" elderly women, and—the clincher, the coup de grease, if you will—of "all-cause mortality" in men. Having an excess of visceral fat has also been implicated in the development of Alzheimer's disease, colon cancer, gallstones, ovarian cystic disease, breast cancer, and sleep apnea.

"Visceral obesity," declares Philipp Scherer, a professor of cell biology and medicine at Albert Einstein and an expert on fat, "does seem to be truly evil."

Yet most people have never even heard of visceral fat. A survey released last year by the World Heart Federation concluded that most Americans are unaware that visceral fat is a leading risk factor for heart disease—even though, by one estimate, almost 46 percent of adult Americans have an excess of it. Moreover, the majority of physicians do not regularly check their patients' girth, which is the primary indicator of visceral obesity. "We are where cholesterol was in 1970 or blood pressure was in 1960," says obesity researcher Steven Smith of the Pennington Biomedical Research Center in Baton Rouge.

Visceral fat lies deep inside the abdomen, surrounding vital organs like the liver, heart, intestines, and kidneys, as well as hanging, in a separate double flap, off the ends of the stomach like an apron. In lean people, the flap, known as the omentum, is thin enough to be seen through (by someone in a position to have a look, that is). In obese people it may be inches thick, fused, and "hard like cake," according to Edward Mun, now director of bariatric surgery at Faulkner Hospital in Boston; he is the surgeon who removed part of Garofolo's omentum. Packed around the organs is another type of visceral fat, called mesenteric.

The abdominal region harbors still another kind of fat, which lies outside the abdominal wall, just under the skin. This subcutaneous, or peripheral, fat tends to be soft and flabby; you can pinch or grab it. It has two compartments, the deeper of which is thought, like visceral fat, to have negative effects on health. The superficial layer may cause cosmetic distress in women who get a buildup of it as they age, but from a medical perspective it is considered benign. Subcutaneous fat also appears outside the abdominal area, on the lower body—the hips, buttocks, and upper thighs. There it is not only benign but actually beneficial.

"Peripheral fat is, in reality, good fat," explains Osama Hamdy, director of the obesity clinic at the Joslin Diabetic Center.

Before menopause, women tend to have more good fat than men do. One interpretation holds that, through most of human evolution, visceral fat was useful for short-term storage—it accumulates quickly and is released quickly—for the benefit of male hunters who needed quick access to energy. Subcutaneous fat, in contrast, was meant for long-term energy storage, for the benefit of the (often female) gatherers who had to wait a long time between meals. Subcutaneous fat is less active metabolically than visceral fat. "It's like a big bucket," Smith says. "It locks the fat in." Put another way, it keeps accepting excess caloric energy that might otherwise end up in the abdomen. Jean-Pierre Després, director of research in cardiology at the Laval Hospital Research Center in Quebec City, calls subcutaneous fat "an expandable metabolic sink."

Compared with women, men not only have "a smaller gluteofemoral [butt-thigh] bucket," notes Smith, but they also have twice as much visceral fat, the stereotypical beer belly. (Approaching menopause, women start to catch up.) The belly may feel hard to the touch instead of soft, the visceral fat pushing up against the muscles of the abdominal wall. Health profiles reflect this sexual dimorphism: Men tend to be less insulin sensitive than women.

One of the first to make this link was Jean Vague, a professor on the faculty of medicine at the University of Marseille. In 1956 he recognized this male-pattern obesity—also called android obesity—and observed that it leads to "metabolic disturbances," including diabetes. Vague was far ahead of his time. "Obesity wasn't a big deal in the '50s," Smith says. "We were dealing with polio." Nowadays a person with android obesity would be called an "apple," while a person with gynoid obesity ("with lower-body predominance," Vague wrote) would be a "pear." As anyone who has read a fitness magazine knows, apples are bad, pears are good.

Visceral and subcutaneous fat are like "two separate organs, each with its own function," Hamdy says. Underscoring the difference are the disappointing results of efforts to improve patients' metabolic states through liposuction. When surgeons took out large amounts of abdominal fat—in one case 20 pounds of it—the patients experienced no improvement in insulin sensitivity. The type of fat that liposuction sucks out happens to be subcutaneous and hence benign; in some cases, the liposuction actually increased the amount of visceral fat, elevating the patients' risk. "It looks as if there's a messenger," Hamdy says. "The two types of fat have a language. Each senses the other."

Unless you have a CT scan or MRI, you cannot know for sure how much visceral fat you have, because it is hidden—but you can get a pretty good idea by measuring your waist. To assess the reliability of this extremely simple diagnostic tool, a committee that included Després supervised an International Day for the Evaluation of Abdominal Obesity in 2005, during which 6,400 primary care physicians in 63 countries gathered the waist measurements and health statistics of 180,000 patients. (Each physician had been sent an instructional video on how measuring should be done: Use bony landmarks, not the navel, because the waist lies midway between the bottom of the lowest rib and the top of the hip bone.) The results, according to Després, were "overwhelmingly clear": The correlation was 97 percent. "The greater the waist circumference, the greater the prevalence of diabetes and heart disease."

Physicians generally recommend that women have waists less than 35 inches around, men less than 40 inches. With the rapid rise in obesity in the United States, the average American woman's waist grew 1.3 inches in the six years between 1994 and 2000, the average man's 1.1 inches. Sumo wrestlers are a colorful and instructive exception. Big, big eaters and artificially obese, they look like prime candidates for heart disease and diabetes and would definitely fail the belt test. Nevertheless, Hamdy reports, they are "extremely insulin sensitive and don't have hypertension." Body scans reveal that sumo wrestlers typically have little visceral fat, presumably because they exercise six to eight hours a day. Most of what hangs over their mawashis is subcutaneous fat. When they retire, however, if they keep eating, their visceral fat balloons.

So what is it about abundant fat deep inside the belly that inclines a person to diabetes, heart disease, stroke, and other ills? Why should having a beer belly be so much worse than having humongous hips, thunder thighs, a well-padded bottom, loglike arms, or an opera-singer bosom? Until recently, adipose tissue was considered passive and inert, simply a place to store energy. Anatomy books often didn't even show fat because it obscured the view of the structures underneath. That changed in 1994 with the discovery of leptin, an appetite-inhibiting hormone, and with the revelation that it is secreted by fat. The following year Philipp Scherer and others discovered adiponectin, a hormone that is protective against diabetes, also secreted by fat.

Since then investigators have found dozens of biologically active substances that are released by fat cells or by cells residing in fat. The list includes immunomodulators, coagulation factors, hormones and prohormones, inflammatory and proinflammatory markers, enzymes, and lipids. Together these substances "have a profound effect on the whole system," Scherer says. Fat is now considered to be an active, complex endocrine organ, like the pancreas.

Of the fat depots, visceral fat is the most active—"very lively," Després says—secreting and mobilizing substances in the greatest quantity. It releases a lot of fatty acids (breakdown products of fat) into the bloodstream through the portal vein and liver, a phenomenon that until recently had been thought of as the major reason why fat promotes insulin resistance. Lately, though, the focus has shifted to fat's link with inflammation.

"When people get older or more obese," Hamdy says, "some of the visceral fat cells mature and become large, lazy, and dysfunctional." As people continue to eat and the fat pads expand, some cells get too full and rupture. Immune cells called macrophages, the janitors of the body, invade the site to clean up. In the process they induce inflammation; the cells also secrete other inflammatory chemicals, like interleukin-6 and tumor necrosis factor-alpha, which are known to adhere to the endothelium of the blood vessels, an early event in atherosclerosis.

"The inflammation isn't what you'd measure in a patient with bacterial infection, which would be 1,000 times higher," Scherer says. "It's subclinical, just a bit higher than background, little needle pricks rather than a sledgehammer blow. But over many, many years of chronic exposure, it can have a negative impact on cardiovascular health and insulin sensitivity."

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.

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