Why leptin is a weight loss bust

It was one of the biggest medical stories of the 1990s and, consequently, one of the biggest disappointments. In 1994, researchers at Rockefeller University, working with mutant mice that grew to be three times the size of normal ones, discovered what made them different: the absence of a hormone they named "leptin."

When injected with leptin the mice suddenly changed their eating habits and began shedding those unsightly grams. Leptin seemed like the long-sought willpower-in-a-pill.

But what worked in mice didn't work in people.

It was a bust because obesity researchers are up against a phenomenally complex and robust system, devised by evolution precisely for the purpose of hoarding fat against the certainty of future famine.

The search for a simple cure for obesity failed for decades, in part because researchers regarded fat as merely the product of an equation whose other terms were greed and guilt. Now they recognize fat tissue as a discrete, active organ in its own right, continuously exchanging messages with the rest of the body by way of the bloodstream.

The messages are, generally, of two kinds: either "I'm full" or "Isn't there a Wendy's two-for-one coupon in the glove compartment?"

"We like to think that eating is a voluntary act," says Dr. Michael Schwartz of the University of Washington. "But the amount you eat is controlled in part by how much fat you have."

The search for a simple cure for obesity is still failing. Ask any researcher, no matter how esoteric his specialty, for the best way to lose weight and he will reply, "Eat less and exercise more."

But now we have a much better understanding of why the search is so difficult—and where we should look, not just to treat obesity as such, but also to recognize that some people are likely to stay fat to minimize the negative effects on their health.

The work begins at the level of the fat cell itself, a glistening oleaginous sphere so tiny that it takes a million of them to store the calories in a Life Saver, yet functioning like little chemical factories continually absorbing or releasing substances in response to the body's energy needs.

"Few systems are more critical to survival," says Dr. Rudolph Leibel of Columbia, than the energy storage-and-management system that includes not just fat but the brain, stomach, liver, pancreas and thyroid. The problem, of course, is that the system evolved millions of years before the first food court made its appearance on earth.

That, says Bruce Spiegelman of the Harvard Medical School, is why it is so much easier for most people to gain weight than to lose it: "For most of evolution, getting enough to eat was a driving force for survival. How many individuals were lost to morbid obesity?"

When calorie intake exceeds expenditures, fat cells swell, to as much as six times their minimum size, and begin to multiply, from 40 billion in an average adult up to 100 billion, the threshold to get your picture on the front page of the supermarket tabloids. (Losing weight causes them to shrink in size and become less metabolically active, but their number goes down only slowly, if at all.)

Some of the resulting problems are familiar, and essentially mechanical. Fat requires a copious supply of blood in tiny capillaries (compared with an equal weight of lean muscle, which is supplied by larger blood vessels); this puts a strain on the cardiovascular system. Obesity creates wear on the joints, leading to osteoarthritis. The accumulation of fat around the windpipe can interfere with breathing when muscles relax in sleep. And fat discourages exercise by reminding the brain: no way am I going out of doors in a jogging suit, unless there's a blackout.

But the discovery of leptin helped create a paradigm shift: increasingly, researchers believe that the biochemistry of fat holds clues both to its tenacity and to the diseases associated with obesity, including heart disease, diabetes and even certain cancers.

Leptin is one of a half-dozen or so chemical messengers produced by fat cells, including thrombotic (pro-clotting) agents, vasoconstrictors (which raise blood pressure) and both inflammatory and anti-inflammatory agents that have powerful effects throughout the body. It just goes to show, says Dr. Gokhan Hotamisligil of the Harvard School of Public Health, "in the human body, as in the world, if you control fuel resources, you influence a lot of other things as well."

Inflammation is getting a lot of research attention right now. In addition to the inflammatory agents it makes directly, fat tissue attracts immune-system cells called macrophages, which promote inflammation on their own. "If you have excess fat, even in small amounts, the body starts mounting an immune response," says Hotamisligil, "almost as if the body is perceiving excess calories as an invading organism." Presumably, this is part of fat's intended function; inflammation fights infection, which for most of history was a more pressing threat than Doritos.

But inflammation is also now viewed as a key mechanism in heart disease—more important than the anatomical narrowing of coronary arteries by cholesterol deposits, which had been the focus of cardiovascular treatment for a generation.

"We're good at diagnosing and treating those blockages," says Dr. Peter Libby, a Harvard cardiologist. "But most heart attacks aren't caused that way. The bigger problem is inflamed plaque that can crack open and cause a blood clot, leading to a heart attack or stroke."

Through a complex sequence of biochemical events, compounds secreted by fat cells contribute to vascular inflammation. And the risk is heightened by two other compounds produced in fat cells: plasminogen activator inhibitor-1, which blocks the body's own clot-busters, and angiotensinogen, which leads to high blood pressure.

At the same time, a high level of fatty acids in the blood—which occurs in obesity—inhibits nitric oxide, a compound that helps relax blood-vessel walls and lower pressure. For anyone thinking of becoming obese, this ought to give them pause.

Fat cells also secrete estrogen, which is linked to certain types of cancer, chiefly breast cancer; in postmenopausal women, obesity is a risk factor. But even more promising is research into the link between obesity and type II (adult-onset) diabetes.

Although most obese people never become diabetic (and not all diabetics are obese), fat is nevertheless a major risk factor for the disease, which damages the blood vessels and can lead to cardiovascular disease and blindness.

Diabetes is a buildup of glucose in the blood, so a natural assumption is that the underlying mechanism is diet: that people get diabetes for the same reason they got fat, by eating too much sugar. But researchers now suspect that the origin of diabetes lies at least partly in the biochemistry of fat. In particular, two compounds made by fat cells—tumor necrosis factor alpha and resistin—seem to interfere with the operation of insulin.

Insulin is the hormone that promotes the uptake of glucose from the bloodstream into the cells, and "insulin resistance" is a precursor of full-blown diabetes. Resistin also has another effect: it apparently promotes the conversion of fatty acids into glucose by the liver, a process that is useful if you're temporarily out of food, but a potential hazard if you're at risk for diabetes.

Resistin's effects are countered by adiponectin, the one truly beneficial compound (in the context of modern society) made by fat. Adiponectin reduces inflammation, increases insulin sensitivity (lowering blood sugar) and even seems to improve the balance of HDL (good) versus LDL (bad) cholesterol. Unfortunately, the fatter you are—that is, the more your fat cells fill up with fat—the more resistin you make... and the less adiponectin.

The point of this research isn't to prove that obesity is bad for you; the evidence of that is statistical, and unassailable. But learning about the biochemical mechanisms at work is the first step in trying to disrupt them. The way TNF-alpha promotes insulin resistance requires an intermediary, an enzyme called JNK. Mice without the gene for making JNK never develop diabetes, no matter how much they're fed, says Hotamisligil.

You can't breed people that way, obviously, but it might be possible to find compounds that block the action of JNK, and researchers are working on it (although they're still far from trying them out in humans). A class of diabetes drugs called TZDs (including Avandia and Actose), originally discovered by trial —and error, has recently been discovered to act on a receptor in fat cells that affects glucose metabolism throughout the body. Obviously, understanding how these drugs work is a major step toward improving them.

The other conceptual breakthrough in recent years has been the unexpected finding that fat cells behave differently in different parts of the body—and, therefore, that an individual's fat distribution has implications for his or her health.

Fat carried in the hips and thighs—the "pear" body shape—is considered comparatively benign, because it is less metabolically active than the kind that accumulates around the organs in the abdomen. (That also, of course, makes it harder to lose weight from the thighs.)

"Visceral fat has the highest association with diabetes, high-blood pressure and high triglycerides," says Dr. Michael Jensen of the Mayo College of Medicine. Visceral fat produces more inflammatory and clot-promoting compounds than the subcutaneous fat distributed around the body.

Fortunately, visceral fat is also the first to disappear when you exercise. It is not, however, susceptible to liposuction; only subcutaneous fat can be removed that way.

Dr. Samuel Klein of Washington University in St. Louis found that even removing 10 kilograms (22 pounds) of subcutaneous fat did not improve the overall health status in a group of obese women; when he looked at their blood chemistry, "everything was the same," he found. "If you'd lost the same amount of fat through diet and exercise, you would shrink the size of the fat cells [everywhere in the body], and they would produce fewer of these chemicals."

By and large, nutritionists have believed that an individual's distribution of body fat is determined genetically. A study by Katherine Tucker, a nutritional epidemiologist at Tufts, however, suggests that where your calories come from might also make some difference.

In her study, participants ate roughly the same number of calories, but those who consumed more white bread, rice, pasta and other refined carbohydrates tended to add fat disproportionately around the middle, even without a big change in weight. Other foods produced little change in waist measurements. These good foods included whole grains, beans, fruits and vegetables.

Meanwhile, research has continued on leptin, in the hope that within the biochemical labyrinth opened by its discovery lies a shortcut path to losing weight. Leptin is made in fat cells; the more fat you have, as a rule, the more leptin you make. Unquestionably it plays a role in the finely tuned feedback mechanism that keeps weight fairly stable in most people—even those who are consistently overweight—without conscious effort.

"It's not just chance," says Schwartz, who points out that if someone consumes a million calories a year, and ends up gaining or losing a pound, "that means your body was 99.6 percent accurate in matching calorie intake to expenditure, which is pretty good."

People (or mice) who don't produce leptin at all eat uncontrollably; normal mice who receive an extra dose of it lose weight. And leptin doesn't just affect eating; Eduardo Nillni of Brown has discovered that a rise in leptin also sets off a sequence of hormone releases that speeds metabolism, burning calories faster. (Conversely, when leptin levels drop, metabolism slows; this is why keeping off weight is so hard.) So why can't a fat person just take a leptin pill and get into a size 8?

No one knows for sure, but a lot of research is going into the concept of "leptin resistance," a hypothetical state in which the brain and endocrine system fail to respond to the increase in leptin that results from gaining weight.

In experiments with mice, Dr. Eleftheria Maratos-Flier of Harvard made them gain weight on a high-calorie diet, and found that their leptin levels increased nearly 10 times—to a level that would cause a mouse of normal weight to stop eating for a day. "If you can do this with a lean body," says her husband, Dr. Jeffrey Flier of Harvard, "why doesn't it happen in obesity?"

Over more than half a decade he has looked for answers, and he's still looking, although he is homing in on a compound called SOCS-3, which seems to inhibit the activity of leptin. High-fat diets seem to promote SOCS-3, a possible mechanism for leptin resistance; drug companies are hard at work looking for drugs to enhance leptin sensitivity.

Of course, it probably won't ever be as simple as that. Leptin itself affects only one mechanism of weight control; the body has many overlapping systems, in a baffling array of positive and negative feedback loops. One of these is the hormone ghrelin, which sends a signal to the brain to eat whenever the stomach is empty and ease up when it's full; some patients are being experimentally treated with electronic "pacemakers" that apparently fool the ghrelin system into thinking the stomach is fuller than it is.

Then there are the pleasure centers of the brain, which certain foods also notoriously target. An experimental drug, rimonabant, has shown considerable promise by disrupting these cannabinoid receptors (so named because they are the same parts of the brain stimulated by marijuana).

"We come up with new drugs on the drawing board all the time, but rarely do they work the way we think they will," says Dr. Elbert Glover of West Virginia University Medical School. "This one did. I think the drug has incredible potential."

And so it might, although many drugs have had "incredible potential" to cure obesity, and you can just look around and see the results. Fat has resisted every chemical attack on it, with the result that more and more people are reduced to mutilating their stomachs in gastric bypass surgery. "Mammals," says Nillni, "are very complex animals."

After all his work on leptin and the thyroid and the hypothalamus, he thinks he knows how to lose weight. The most practical solution for now, he says, is not to fight the basic biology of the fat cell.