Posted Sunday, June 29, 2003; 14:08BST
Although leptin has since been dismissed as an obesity treatment — the vast majority of obese people turn out to have normal leptin levels — its discovery touched off a scientific gold rush that has yet to abate. Competing research teams in the U.S. and Europe have so far identified at least half a dozen other compounds that have surprising power to regulate appetite. Researchers at London's Imperial College of Medicine showed last year that one of those hormones, dubbed PYY3-36, which is released in the small intestine after a meal, actually promotes a sense of fullness. Each of these compounds is slightly different, and scientists are just beginning to figure out how they all work together. What is clear is that all of them are important nodes along an elaborate network of interconnecting pathways that feed into, and out of, the hypothalamus, a brain structure that is the control center for weight regulation. The body produces hormones that activate the hypothalamus. The neurons in the hypothalamus send new messages back to the body. And just like subliminal messages spliced into a filmstrip, these signals powerfully affect our behavior even when we are not aware of them.

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 to 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 year pinpointed three genes that may account for at least some of that variation. Mice that lack the genes, they reported in the journal 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 up to 70% of 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 in consuming and storing more calories than they expend. In this fashion, the body creates 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 80 kg will take in 1 million calories a year on average and will also expend 1 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. With fast-food outlets lining our streets and time- and labor-saving gadgetry proliferating, the energy balance is increasingly tipped in favor of fatness. We expend less than a calorie every time we change channels using the remote control. If we'd only get up and go over to the TV, we'd use three. Using a car wash consumes 18 calories, while washing and waxing the car yourself consumes 300. "It is the minimal amount of energy you need to get through daily life in a European city that has made a huge impact," says Dr. Simon Coppack, who runs an obesity clinic at St Bartholomew's and Royal London Medical School.

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