Thus, while we read the paper or carry on a conversation, the hypothalamus—activated by leptin or some other compound—orders cells and tissues to ratchet up energy expenditure. The body responds by idly fidgeting to raise metabolic rates, or by increasing blood flow to the outer layers of the skin in an effort dissipate heat. In this way, we carry out a process known as thermogenesis, which is the body's way of burning excess calories.

Intriguingly, some people seem to be more efficient at thermogenesis than others. Researchers led by Dr. Bradford Lowell at Beth Israel Deaconess Medical Center in Boston last month pinpointed three genes that may account for at least some of that variation. Mice that lack the genes, they reported in Science, grow grossly obese when fed a high-calorie diet enriched with fat and sucrose. By contrast, normal mice fed the same diet gain very modest amounts of weight.

The fact that obesity has genetic roots does not explain the larger mystery. If obesity is so bad for us—and there is no question it is—then why are so many people susceptible to layering on excess fat? The answer may well lie in what is referred to as the Thrifty Gene Hypothesis, which supposes that obesity genes have been maintained in the human population because they conferred an appreciable survival advantage.

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Rather like the ant in an Aesop's fable, people with thrifty genotypes—wisely, it might be argued—prepare for hard times by consuming and storing more calories than they expend. In this fashion, they create a reservoir of fat that comes in handy when food grows scarce. It's easy to imagine that repeated famines over the course of human development practically forced the biological system for regulating weight to skew strongly toward resisting weight loss rather than protecting against weight gain.

In principle, at least, no one should ever become obese. That's because the genetic system for regulating weight would seem to be exquisitely tuned. Researchers calculate that a man who keeps his weight stable at 175 lbs. will take in a million calories a year on average and will also expend a million calories. "Think about it," says Dr. Michael Schwartz, head of clinical nutrition at the University of Washington in Seattle. "How do you match a million with a million? It doesn't happen just by chance."

Leptin, which exercises an influence on appetite and thermogenesis, is thought to be key to maintaining this balance. For as we layer on fat, we pump out more leptin, which signals the hypothalamus that it's time to accelerate energy output and brake caloric intake. The problem is, people who gain weight have now been shown to develop a remarkable resistance to leptin's power. The fatter they get, and the more leptin they make, the more impervious the hypothalamus becomes. Eventually the hypothalamus interprets the elevated level of leptin as normal—and forever after misreads the drops in leptin caused by weight loss as a starvation signal. This phenomenon provides a biochemical explanation for why so many of those who lose weight end up putting it back on. Our bodies, backed by millions of years of evolution, fight us at every turn.

So what causes leptin resistance? The answer may turn out to be exceedingly complicated. Not only do the other hormones of the digestive system play a role, but also researchers are learning that they must account for the influence of such mood-altering neurotransmitters as dopamine and serotonin, as well as the stress hormones adrenaline and cortisol. And then there are melanocortins, brain chemicals whose power to affect weight loss and gain is just now coming into focus.

Genes, of course, do not make us fat. They merely set up a susceptibility to gaining weight under certain conditions—and without question, those conditions are now ubiquitous. In essence, says Dr. Walter Willett of the Harvard School of Public Health, sedentary lifestyles and a cornucopia of food have transformed people into the equivalent of corn-fed cattle confined in pens. "We have created the great American feedlot," he says.

Our Stone Age ancestors certainly did not live in a feedlot. They had to kill and butcher their meat-on-the-hoof during marathon hunts that lasted for days, sometimes weeks. They had to ramble for miles cross-country to gather wild fruits, grains and nuts and to dig underground tubers. If they wanted to eat something sweet, they had to locate a beehive, smoke out the bees and retrieve the honey, often by climbing up a tree or chopping it down.

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