The change has been so swift and so pervasive that no simple explanation is possible. Maybe we didn't understand all the ramifications when we jumped on the low-fat bandwagon. We also failed to factor in suburban sprawl and six-lane expressways, school cafeterias and fast-food chains, movie theaters and television, advertisers and food processors. "We live in a toxic environment," says Kelly Brownell, director of the Yale University Center for Eating and Weight Disorders. "Physical activities have been engineered out of day-to-day life, and the food environment grows worse by the day. We took Joe Camel off the billboards, but we celebrate Ronald McDonald."

On one level, there is no mystery about why we as a society are fat. We are fat because we consume too many calories and expend too few. Though it is true that the proportion of fat in our diet has fallen from 40% in 1990 to roughly 34% today, the calories available in the food we consume have gone up, from 3,100 calories per capita per day in the 1960s to 3,700 in the 1990s, according to the U.S. Department of Agriculture (USDA). "And that alone," says New York University nutritionist Marion Nestle, "is sufficient to explain the obesity epidemic."

But there is a deeper question—one that has plagued anyone who has ever struggled to take off more than a few pounds. And that is: How do some folks manage to live in the same "toxic environment" and never gain weight? Indeed, the question of why so many of us are fat is just half the puzzle. "You can just as easily flip it around," says Jeffrey Friedman, a molecular geneticist at Rockefeller University, "and ask why—despite equal access to calories—is anyone thin?"

The quest to answer this double-sided question is in its earliest stages. Already, however, a series of fascinating insights into the biology of obesity has emerged. Behind our broadening behinds and widening waistlines, scientists say, lies a complex array of genes that, directly and indirectly, links our gut to our brain. These genes, honed by millions of years of evolution, appear to have betrayed many of us in the 21st century world.

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. 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.

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