Fat: more than just a lump of lard.

America is getting fatter. We're too big not only for our britches, but for our airplane and stadium seats ... and for our health. As the obesity epidemic spreads, researchers have learned that fat is more than an extra layer of padding or insulation. It's an endocrine organ--just like the thyroid, pancreas, or adrenal gland--that sends signals to influence how the body works.

What's more, not all fat is equal. Depending on where it's deposited, fat may be easier or harder to get rid of and worse or not-so-worse for your risk of diabetes and heart disease.

We may be getting fatter, but when it comes to fat, we're also getting smarter.

The breakthrough came in 1994.

That's when Jeffrey Friedman's research team at Rockefeller University discovered leptin, a hormone secreted by fat cells that controls fat stores and much more.

"It's not at all surprising that fat isn't passive," says Friedman. "Much of our survival depends on our ability to get nutrition just right, so there are a lot of signals in a complex network designed to do just that."

For example, if a woman has too little body fat to successfully carry a baby to term, her fat cells may signal her brain to stave off pregnancy.

For most of human history, though, survival meant avoiding starvation, not a supersized belly. Unfortunately--at least for people who are tempted with food every time they walk (or, more likely, ride) to a shopping mall, gas station, drugstore, or movie theater--our bodies are set up to deal with scarcity, not abundance.

"The body has lots of ways to respond to overindulgence," says exercise physiologist Cris Slentz of Duke University. "They're all the result of too much food and too little activity."

Swollen Fat Cells

When we eat more calories than we burn, the body converts most of the excess to fat. Where does the fat go? "It's got to be stored somewhere," says Slentz.

First, so much gets stuffed into our fat cells (also called adipose cells) that they swell. That's problem No. 1.

Fat cells secrete more than a dozen proteins that trigger changes throughout the body. And when fat cells expand, they release more of some proteins and less of others. For example:

* Leptin. "People originally were taken by the notion that leptin might be the cure for obesity," says cell biologist Philipp Scherer of the Albert Einstein School of Medicine in New York.

Leptin sends signals to tell the brain whether to boost or curb appetite. "The more fat in the body, the more leptin that circulates," explains Scherer.

In theory, extra leptin should rein in appetite and burn more calories. But so far, it doesn't appear to be the anti-blubber drug of our dreams.

Swallowing leptin in a pill doesn't help the overweight because, like any other protein, it gets digested in the gut before it reaches the bloodstream. And even if leptin is injected, it doesn't curb appetite and burn more calories.

"People who are obese are not sensitive to leptin," explains obesity expert Samuel Klein of Washington University in St. Louis. They have plenty, but they don't respond to it.

"It's possible that leptin may help maintain weight loss after people lose excess weight," says Klein, but it's too early to know.

Meanwhile, leptin can work against the dieter. Lose enough weight and your fat cells shrink, which means they release less leptin.

"When leptin levels drop, the brain sees that as evidence of starvation and it causes you to be hungry," says Scott Weigle, professor of medicine at the University of Washington School of Medicine in Seattle.

It's a Catch-22. "Leptin levels fall as you lose weight, and that tends to promote weight gain because the fall is a stimulus to eat more and burn less," says Friedman.

Burning fewer calories makes it harder to lose weight. "The tragedy is that when you reduce the number of calories you take in, you become much more efficient at using them," says Scherer. "Once you get off the diet, you're still using calories efficiently, so people gain so much back that they often overshoot their original weight."

* Adiponectin. "Larger fat cells are associated with insulin resistance," says Klein. And adiponectin--a protein secreted by fat cells--helps explain why.

Insulin admits blood sugar into the body's cells, where it's stored or used as fuel. Many overweight people produce plenty of insulin, but the hormone loses its punch. This "insulin resistance" can lead to high blood sugar levels and raises the risk of heart disease even if it doesn't cause diabetes (see "Insulin Alert").

"The more fat you have, the less adiponectin your fat cells produce," says Scherer, who discovered adiponectin.

Adiponectin is low in anyone who's overweight, but it's especially low in people who are insulin resistant, which suggest that it makes the body responsive to insulin.

"Adiponectin is a good-buy hormone," says Weigle.

So far, no one has tried to inject adiponectin into people, but even if they could, it would mostly affect insulin resistance, not spare tires.

* Inflammatory Proteins. The larger your fat cells, the more they stir up the immune system. "Fat cells put out cytokines like interleukin-6 and especially tumor necrosis factor-alpha," says Slentz. "They increase inflammation."

The inflammation is too subtle to cause a fever, pain, or any other sign of trouble. But it's still insidious.

"Inflammation causes the plaques that clog arteries to begin rupturing," says Slentz. "That's when people have heart attacks."

All the Wrong Places

"There's only room for about 1.2 micrograms of fat per cell," says Klein. "The cells get bigger, but not huge. They don't get big enough to store, say, three micrograms of fat."

Cells that can't get any bigger do what anyone looking for more storage space would do. "If people continue to consume more calories than they burn, they make more fat cells," says Scherer.

People used to think that only babies could make new fat cells. "There was a notion that if you gain too much weight in the first two or three years of life, you would be fat for life," says Scherer. "Now that notion has been dispelled."

In fact, a chubby teenager is more likely than a chubby toddler to become an obese adult.

That's good news for parents of young children, but bad news for everyone else.

"Now we know that people can make new fat cells at any age," says Scherer. "And while loading up a fat cell with more fat is quite reversible, once you make more fat cells, they're going to be around for a very long time."

"The half-life is probably at least a year, but I think it's longer," he notes. "Once you've accumulated a number of fat cells, they may be there to stay. If you put yourself on a diet, you primarily reduce the amount of fat stored in a cell," not the number of fat cells.

And in many people, even new fat cells aren't enough to store the excess fat. So it starts going places that it's not supposed to, like the liver, muscles, and maybe the pancreas.

"In muscle, you can see fat cells interspersed between muscle cells," says Scherer. "It looks like the white veins that you see in a marbled steak."

That misplaced fat seems to lead to insulin resistance. "People with diabetes have low-density muscle because so much fat is stored there," says Slentz.

Endurance athletes are an exception, he adds. They store fat in their muscles without any apparent harm.

But for most people, says Klein, "the more fat we store in muscle, the liver, and the heart, the more abnormalities we see in those organs."

Gut Issues

Dumping fat into fat cells is less harmful than stashing it in muscles, the heart, and other organs. But where those fat cells are also makes a difference.

People who gain weight around the middle (so-called "apples") have a higher risk of heart disease and diabetes than people who gain weight in the hips and thighs ("pears"). Men are more likely to be apples. Younger women are usually pears, but move closer to apples as their weight shifts after menopause.

"Premenopausal women put fat on their thighs or the backs of their arms," explains Slentz. "Those are good places to store it because it doesn't cause insulin resistance." (Women may beg to differ, of course.)

Researchers are trying to figure out why apples are at greater risk. Fat that's stored deep in the abdomen may hold the answer.

"On average, 80 to 90 percent of fat is subcutaneous, or lust under the skin," says Klein. "The remaining 10 to 20 percent is the visceral fat that's deep inside the abdomen and the fat in non-adipose tissue like muscle, liver, and heart."

Researchers aren't sure why visceral fat is so much worse.

"It's very active," says Scherer. "And it releases free fatty acids that cause inflammation and insulin resistance." Visceral fat also secretes more inflammatory agents like interleukin-6 and tumor necrosis factor-alpha.

Another theory: "Visceral fat is close to the liver and pancreas, so when you move fat out of the fat cells, it goes directly to those organs," says Slentz.

Limits of Liposuction

When people lose weight, they lose both visceral and subcutaneous fat. And that lowers their risk of heart disease and diabetes. Not so when the fat is vacuumed out of them.

Klein and his co-workers recently used liposuction to remove roughly 20 pounds of subcutaneous fat from the bellies of 15 obese women. (1)

The result: "If you lose fat by liposuction, it improves only the cosmetic problem," says Klein.

Losing 20 pounds of fat had no impact on the women's metabolic health--their insulin resistance, adiponectin, or inflammatory proteins (C-reactive protein, interleukin-6, or tumor necrosis factor-alpha). Nor did the weight loss improve their blood pressure, blood sugar, cholesterol, or any other risk factors for heart disease. Zip.

In contrast, says Klein, "losing as little as five percent of your weight by eating less and increasing physical activity can lower insulin resistance, blood pressure, cholesterol, and the risk of diabetes."

Why so much metabolic bang for your buck? When people lose weight by diet and exercise, they run a calorie deficit--that is, they burn more calories than they take in.

"That causes fat to leave your fat cells, which makes them shrink," says Klein. "And you remove fat from your muscles and liver, which may also help. If you reduce fat by sucking it out, you change the number, but not the size, of fat cells."

The trick, says Klein, is keeping the weight off. "That's the Achilles' heel for most dieters."

Strategies

If liposuction doesn't lower your risk of disease, what does? Getting off your duff is first on the agenda.

"In our study, overweight men and women who averaged 30 minutes of vigorous exercise six days a week for six months lost eight percent of their visceral fat," says Slentz, describing research he conducted with Duke University's William Kraus and others.

"Vigorous" isn't as intimidating as it sounds. "No one actually ran," says Slentz. "They walked on a treadmill on an incline at a brisk pace or used an elliptical trainer," an exercise machine that's even less stressful than a treadmill.

The intensity was equivalent to jogging, he adds, "but we don't recommend jogging to people who are overweight."

What stunned the researchers wasn't the fat loss in the exercisers, but the fat gain in the sedentary "control" group. (2)

"The controls got much worse than we expected," says Slentz. Visceral fat jumped six percent in the men and 12 percent in the women, and they gained an average of about two pounds.

"People think inactivity is a holding pattern," he notes. "But if you gain two pounds in six months, think what you would look like in 10 years. We haven't figured out how to lose weight and keep it off, but if we can just prevent weight gain, that's half the battle."

Researchers see less of a weight gain looking at all adults, not just the obese, but it's still troubling. "Between the ages of 20 and 40, Americans gain about two pounds a year," says obesity researcher Xavier Pi-Sunyer of Columbia University. "That's 40 pounds over 20 years. It's incredible."

And it's not just a question of going up a dress size, says Slentz. "After six months, we saw an increase in the controls in insulin resistance and an increase in small, dense LDL particles," which are the most likely to clog arteries.

Surprisingly, Slentz didn't have to drag people kicking and screaming to the treadmill. "It's extremely easy to recruit overweight people for these studies," he says. "They desperately want to exercise, but they know they need help to get started."

Once they begin, most people keep with it because they feel and look better. "Even if people don't lose much weight, they like being trimmer and less flabby," says Slentz.

His participants might have lost more weight if they had also cut calories. Alice Ryan and co-workers at the University of Maryland School of Medicine put 37 overweight or obese women on a lower-calorie diet for six months. (3) The women also walked at moderate intensity on a treadmill for 45 minutes three times a week.

"This wasn't a crash diet," says Ryan. "They lost 10 percent of their body weight in six months--about half a pound to a pound a week--so it was certainly achievable." Along with the weight, the women walked off 17 percent of their visceral fat.

What's more, says Ryan, "their levels of pro-inflammatory proteins fell. That may explain why their insulin resistance dropped."

What You Eat

Clearly, how much you eat makes a difference to your fat cells. Could what you eat also matter? It's too early to say, but a few researchers have come up with intriguing results.

"Our study showed very significant weight loss over three months without restricting calories, just by changing people to a very-low-fat diet," says Scott Weigle of the University of Washington School of Medicine in Seattle.

"That's nothing new," he explains. "We know from studies on the Pritikin and Ornish diets that very-low-fat diets lead to weight loss."

What's new is the diet's impact on leptin. (4) "Leptin levels dropped, as expected with weight loss," says Weigle.

"But the participants didn't complain of being hungry, so we infer that the brain's sensitivity to leptin increased."

What's more, his subjects showed no rise in ghrelin, a hormone released by the stomach that spurs hunger. "A rise in ghrelin occurs with weight loss if you achieve it by any other diet," says Weigle.

If his study is confirmed by others, it may mean that a very-low-fat diet somehow skirts the usual pitfalls--like a drop in leptin and a rise in ghrelin-that make it so hard for people to keep weight off.

Whether people can stick to a very-low-fat diet is another question. "To successfully implement it takes nothing short of remaking your life," says Weigle.

The Bottom Line

Though scientists know more than ever about fat, they have yet to find the magic bullet to keep us happily slender and shaped like movie stars, not fruit.

In fact, some researchers are even more convinced that, for some people, severe obesity is hard-wired.

"People who have a gastric bypass markedly reduce their intake to 700 calories a day," explains Rockefeller University's Jeffrey Friedman. "I'd be a rail if I ate only that much. These people lose weight but they're still obese because their metabolism slows so much."

It's fine to encourage people to lose weight, he adds. But we have to be much less judgmental about the fact that many people fail over the long term.

"The public needs to recognize that there is a real biological difficulty in maintaining substantial weight loss," says Friedman.

Fortunately, most people don't have to lose as much weight as someone who is severely obese. And when it comes to health, you don't need to lose every excess pound.

"Even a ten-pound weight loss can have important health benefits," says Friedman. "And that's achievable for most people."

The other take-home message: it's far better to not gain weight in the first place. "That's the real public health issue," says Columbia University's Xavier Pi-Sunyer. "Given our toxic food environment, we need to teach people to be restrained eaters."

And we need to change an environment where calorie-dense food is thrust under our noses 24/7. "Like any epidemic, we need to change the environment," says diabetes researcher Eric Ravussin of the Pennington Biomedical Research Center in Baton Rouge, Louisiana.

"If you have malaria, you drain the swamp. If you have death on the roads, you impose seatbelts. Maybe we need to tax junk foods to get people to subsidize healthy foods."

Leptin

Gain weight and your fat cells release more leptin. In theory, that should make you eat less and burn more calories. But the fatter you get, the less your leptin works. When you lose weight, your fat cells release less leptin. That makes you eat more and burn fewer calories, which makes it tougher to keep the weight off.

Ghrelin

When you lose weight, your stomach (not your fat cells) releases more ghrelin, which makes you hungry and makes it tougher to keep the weight off.

Adiponectin

This "good guy" hormone enables insulin to hustle sugar from the bloodstream into your body's cells, where it's stored or burned for fuel. The more fat you have, the less adiponectin your fat cells secrete.

Inflammatory Proteins

Fat cells release proteins (like interleukin-6 and tumor necrosis factor-alpha) that cause low-level inflammation throughout the body. Inflammation can rupture the plaques that clog arteries, leading to a heart attack or stroke.

Diet Digest

Low-carb or low-fat? Researchers still don't know which diets am best for keeping weight off over the long term Until more results are in, look for a healthy hybrid like the South Beach Diet. Our basic advice:

* Less bad. Cut back on calories from bad fats and bad carbs. (That includes french fries, burgers, pizza, movie-theater popcorn, nachos, sweets, etc.)

* More good. Build your diet around vegetables, seafood, poultry, low-fat dairy foods, beans, and whole grains, plus some oils, nuts, and other unsaturated fats.

* Eat half out. With most restaurant meals in the 1,000-calorie range, think about ordering one entree for every two people (or taking half home).

Insulin Alert

If you have any three you
have the metabolic syndrome (also known as the insulin
resistance syndrome), which raises your risk of heart disease
and diabetes. The underlying cause: too much weight and
too little exercise.

1. Abdominal obesity      Women: more than 35-inch waist
                          Men: more than 40-inch waist *
2. Triglycerides          150 or higher
3. HDL cholesterol        Women: under 50
                          Men: under 40
4. Blood pressure         Systolic: 130 or higher or
                          Diastolic: 85 or higher
5. Fasting blood sugar    110 or higher **

* For some men, a 37- to 39-inch waist can be a risk factor.

** Recent recommendations classify a fasting blood sugar of 100 to 125
as "pre-diabetes."

Source: National Heart, Lung, and Blood Institute.

(1) New Eng. J. Med. 350: 2549, 2004.

(2) Arch. Intern. Med. 164: 31, 2004.

(3) Diabetes Care 27: 1699, 2004.

(4) J. Clin. Endocrinol. Metab. 88: 1577, 2003.