July 6, 2004
Fat: The Secret Life of a Potent Cell
hey are the building blocks of flab, the wages of cheesecake, the bloated little sacks of grease that make more of us - more than we can fit into our pants. Scorned and despised, they are sucked out surgically by the billions from bulging backsides, bellies and thighs.
But they are not without admirers.
"Fat cells are beautiful cells to look at," said Dr. Philipp E. Scherer, an associate professor of cell biology and medicine at Albert Einstein College of Medicine in New York. "I've been working with them for 10 years and I still enjoy looking at them."
On a recent afternoon at his laboratory, Dr. Scherer slipped a Petri dish of fat cells under a microscope and showed a visitor how strikingly they caught the light and reflected it. Magnified, the cells became a field of glittering rings. A mature fat cell, or adipocyte, contains a huge, clear droplet of fat that takes up nearly the entire cell and shoves the nucleus aside, squashing it up against the membrane so that the cell appears empty. But it's actually a shining sea of fat, stored as molecules of triglyceride.
Scientists used to think body fat and the cells it was made of were pretty much inert, just an oily storage compartment. But within the past decade research has shown that fat cells act like chemical factories and that body fat is potent stuff: a highly active tissue that secretes hormones and other substances with profound and sometimes harmful effects on metabolism, weight and overall health.
In recent years, biologists have begun calling fat an "endocrine organ," comparing it to glands like the thyroid and pituitary, which also release hormones straight into the bloodstream. But there is an important difference. Those glands cannot grow nearly as much as fat, which has a seemingly infinite capacity to make more of itself. Too much body fat can act like a poison, spewing out substances that contribute to diabetes, heart disease, high blood pressure, stroke and other illnesses, including some cancers.
Researchers trying to decipher the biology of fat cells hope to find new ways to help people get rid of excess fat or, at least, prevent obesity from destroying their health. In an increasingly obese world, their efforts have taken on added importance.
Internationally, more than a billion people are overweight. Obesity and two illnesses linked to it, heart disease and high blood pressure, are on the World Health Organization's list of the top 10 global health risks. In the United States, 65 percent of adults weigh too much, compared with about 56 percent a decade ago, and government researchers blame obesity for at least 300,000 deaths a year. Fifteen percent of children over 6 are overweight, three times the percentage in 1980. Obesity rates are highest among black and Hispanic women, and the fastest growing group of obese people are the very heaviest, who are more than 100 pounds overweight. The incidence of Type 2 diabetes, which is almost always caused by obesity, has also been climbing in the United States and other countries.
The recognition that fat cells were far from inert came in 1995 with the discovery of leptin, a hormone that signals to the brain how much fat the body has, so that the brain can adjust eating and metabolism to keep the fat stores at a certain level. The more fat a person has, the higher the level of leptin. Although researchers initially thought that leptin might be used to treat obesity, they soon found that most obese people are resistant to its effects.
"The discovery of leptin established the fat-to-brain communication axis," Dr. Scherer said. "It was the first example of an actual hormone being released from the adipocyte itself. Then life went on, and we and others discovered additional molecules."
Fatty tissue is riddled with immune system cells called macrophages, which pour out substances that cause inflammation, now thought to play a role in heart disease. The fat cells themselves make additional hormones that affect the body's sensitivity to insulin and are closely tied to the development of Type 2 diabetes. Insulin helps move glucose into cells, but about half of obese people become resistant to insulin, meaning that their cells do not respond properly to it. The more weight they gain, the more insulin resistant they become. Insulin resistance is the first step on the path to diabetes and often goes along with high blood pressure and high levels of fats and sugar in the blood.
One of the most important molecules made in fat cells is a hormone called adiponectin, which makes the body more sensitive to insulin. When people become obese, their fat cells make less adiponectin, though it is not clear why. Lowered levels are associated with both diabetes and heart disease. Dr. Scherer said scientists are studying the hormone to find out whether giving it to people can help to prevent or treat diabetes.
Another fat-cell molecule, resistin, makes the body more resistant to insulin, but it has been studied mostly in mice, and its importance in people is not known, Dr. Scherer said.
A lean adult has about 40 billion fat cells, an obese one at least two to three times that, and obese people have much larger fat cells than lean ones. Even worse, the body can always make more, and compared with other cells they are extremely long-lived. Though widely believed, it is not true that a person's quota of fat cells is fixed forever sometime in childhood. Adults do not create new fat cells as readily as children do, but it happens. If a person keeps overeating, the existing fat cells grow and grow, looking as if they are about to pop, but there is a size limit. When they reach that limit they do not divide, but instead send out a signal to nearby immature cells to start dividing to produce more fat cells.
It has been known for decades that some kinds of obesity are worse than others. Body shape matters. People who are shaped like apples, carrying excess weight in the abdomen, are more likely to have diabetes and heart disease than are those built like pears, who deposit fat in their hips, thighs and backsides. A person's tendency to store fat in one place or the other is probably genetic, researchers say, though virtually everybody will develop a big belly as the amount of excess weight rises.
Women tend to be pears but they also redistribute fat and thicken in the middle after menopause. Ethnic groups vary. For instance, Asians are more likely than other groups to put weight in the abdomen and to suffer health problems from lesser degrees of obesity.
Even a little too much abdominal fat - an outsize gut on an otherwise skinny person - can increase the risk of high blood pressure, diabetes and heart disease. Thin or average looking people who actually are at risk from belly fat may be falsely reassured by having a normal reading on a common measurement of obesity, the body mass index, or B.M.I. The problem is that the index, based on height and weight, does not take body shape into account.
"We would like to eliminate the idea that B.M.I. is the best indicator of risk," said Dr. Osama Hamdy, director of the obesity clinic at the Joslin Diabetes Clinic, in Boston. He said waist measurement is a better predictor, with the danger zone being anything greater than 40 inches in men and 35 inches in women.
Why should a big belly be more dangerous than a big backside? Many researchers think the culprit is visceral fat, meaning deposits inside the abdomen, as opposed to subcutaneous fat, under the skin. An apple-shaped person is sure to have visceral fat, as well as subcutaneous fat in the abdominal area. Anybody with a belly has visceral fat, and the more you have the worse off you are. It is not clear why visceral fat is riskier; it may be more active metabolically and spew out more toxic substances. In addition, its secretions go straight to the liver and may interfere with its functions, which include helping to regulate blood glucose and cholesterol.
Some studies even suggest that the cells in visceral fat are uniquely active because they differ from other fat cells when it comes to which genes are turned on or off.
A study published last month in the New England Journal of Medicine lent support to the notion that visceral fat is more of a threat than fat under the skin. Doctors found that liposuction, which removes only subcutaneous fat, had no effect whatsoever on health, even when surgeons sucked out 20 pounds of subcutaneous abdominal fat. But a person who lost that much weight through dieting and exercise would almost certainly see significant changes in blood pressure, cholesterol and insulin resistance.
Besides leaving visceral fat untouched, liposuction may fail to improve health for another reason, said the first author of the study, Dr. Samuel Klein, director of the Center for Human Nutrition at the School of Medicine at Washington University in St. Louis. He said that while liposuction removes billions of fat cells it does not shrink the many more it left behind. Obese people have huge fat cells, with 50 percent to 75 percent more mass than fat cells in lean people, Dr. Klein said. Large fat cells are not a good thing to have because research has found that they are more active metabolically than small ones, and more likely to churn out harmful substances.
The best way to get rid of visceral fat and shrink fat cells all at once is diet and exercise. Even a small amount of weight loss, about 7 percent of total body weight, helps. Researchers do not fully understand why, but there is something about burning more calories than you eat, creating a state of negative energy balance, that quickly begins melting away the mass of visceral fat and slimming down bloated fat cells. Indeed, most dieters find that belly fat comes off first and that weight in the hips and thighs is much harder to lose.
Unfortunately, diet and exercise have high failure rates. Even those who do manage to lose weight often regain it.
Since visceral fat is harmful and many people cannot lose it on their own, researchers have been experimenting with surgical removal. Studies in animals show that blood fats and other risk factors quickly improve when the fat is taken out.
In people, not all of the visceral fat can be removed safely because of where it is situated. But a portion called the omentum can be taken out relatively easily, according to Dr. Edward Mun, a surgeon at Beth Israel Deaconess Medical Center in Boston. It is a pad of fat weighing two to four pounds that hangs like a curtain in the abdomen. "We estimate that it's more than one-third of the visceral fat," Dr. Mun said.
He is doing a pilot study, performing the surgery in six obese, diabetic patients to see if it can reverse their diabetes. The patients are not heavy enough to quality for stomach stapling or other weight-loss operations.
"There is no suggestion that we can achieve weight loss," Dr. Mun said. "So is this worth doing solely to treat diabetes? What if the patient still has sleep apnea and hypertension? We don't know. If they remain obese, they may have a return of diabetes."
The purpose of the study is to develop a better understanding of what visceral fat contributes to diabetes, he said.
"There has been no real direct study on humans to see if visceral fat contributes,'' he said. "We can study the removed tissue for the _expression_ of certain hormones. Why is visceral fat bad? How does it work on the molecular level? What's different about this patient's fat? How different are they genetically?"
Dr. Mun said it was too soon to tell whether the operation was helping.
For other patients, those who are 100 pounds or more overweight, he frequently performs gastric bypass surgery, which shrinks the stomach and rearranges the small intestine to help patients lose large amounts of weight. The operation quickly reverses diabetes and lowers risk factors for heart disease. It works in large part by forcing patients to eat less - to exist in the state of negative energy balance that gets rid of visceral fat.
"It's a relatively primitive operation, but it's quite effective, works for all, gets them better,'' Dr. Mun said. "It's the best thing we have. But I do not want the operation still to be around 100 years from now. To treat obesity, we have to understand how it arises. I really want to understand obesity."
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