NYTimes.com Article: Fat: The Secret Life of a Pot...

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Fat: The Secret Life of a Potent Cell

July 6, 2004

By DENISE GRADY

They 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.

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. 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. "

http://www.nytimes.com/2004/07/06/science/06fat.html?

ex=1090157933&ei=1&en=e6a24f1068d7bbb6

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