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Scientists have long suspected that human beings come into the world equipped with dozens, perhaps hundreds, of genes and associated hormones that regulate what scientists call the energy-balance equation. On one side of the equation are the calories we consume. On the other side are the calories we burn--through physical activity as well as whatever is needed just to keep the body in good working order. Anything left over gets converted to body fat.
With the notable exception of insulin, which helps the body process sugars from carbohydrates, the identity of most of the major players in this biochemical balancing act could for years only be guessed at. The first big breakthrough occurred in 1995, when the Rockefeller's Friedman stunned the scientific world by announcing that he and his colleagues had discovered a hormone produced by fat cells that actually caused fat to melt away, at least in laboratory mice. Genetically engineered mice that lacked the gene for making this hormone developed ravenous appetites and became grossly obese. When these same mice were injected with the missing hormone, they shrugged off a third of the weight they had gained. The researchers dubbed the new hormone leptin, after leptos, which is Greek for thin.
Although leptin has since turned into something of a disappointment as an obesity treatment for humans--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 just last month that one of those hormones, dubbed PYY3-36, actually promotes a sense of fullness after a meal.
Each of these compounds is slightly different, and scientists are just beginning to figure out how they all work together (see diagram). 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 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.