What You Don't Know About Fat

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. Not since Charles Atlas had there been such a convincing set of before-and-after pictures; to millions of Americans who secretly identified with the tangerine-size balls of fur, leptin seemed like the long-sought willpower-in-a-pill. But what worked in mice didn't work in people?-or, rather, it worked only in a handful of people who, like the mice, lacked the gene to produce leptin on their own. For a young woman in England who had weighed 207 pounds at the age of 9, it has been a lifesaver. For everyone else who thought it might succeed where low-carb diets, low-fat diets, Slim-Fast and Richard Simmons had failed, it's been a bust.


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."