Health & Medicine / Obesity

Genes, a virus, lethargy, or just too many fries: the possible causes of obesity are legion.

John Rossi was a model employee at Kragen Auto Parts in Berkeley, California. In his ten years there, first as a clerk and then as a manager, he had missed only three days of work and had regularly put in 50- to 60-hour weeks. So it was something of a surprise when Rossi's manager told him one day in 1991 not to come to work anymore.

A spokesman for the store later said that Rossi was fired for poor job performance. But the only reason Rossi could see for his dismissal was his weight. A high school football star, Rossi had struggled with obesity throughout his adult life. By the age of 21, when he started working at Kragen, he weighed 275 pounds. Over the next decade he tried everything from fasting to hypnosis and at one point had his jaws wired shut. On the day he was fired, Rossi weighed about 400 pounds.

Still, laudatory letters from customers and the company’s own evaluations were clear: weight had never affected Rossi’s job performance. So he decided to sue. Years later, in 1995, jurors awarded him $1,035,652 for lost compensation and emotional distress. They concluded that Rossi couldn’t legally be dismissed for a condition beyond his control. What convinced them, says Rossi’s lawyer, Barbara Lawless, was testimony from a medical witness that each person’s weight is controlled primarily by genetics—he attributed 80 percent to genes and only 20 percent to environment. [CK]

The jury’s decision reflects a profound shift in the way our culture views people who are excessively overweight. No longer can we equate significant weight with lack of willpower. With every passing month now, scientists announce the discovery of new genes and gene neighborhoods that can be associated with obesity. The count is up to 130 and climbing. In each of us, these genes combine to produce different results. Richard Atkinson, an obesity researcher at the University of Wisconsin in Madison, says, “If you think about all the combinations and permutations of those 130 genes, there are going to be dozens, hundreds, thousands of different kinds of obesity.” But knowledge is power, too. An understanding of the genetics of weight control is helping researchers develop a new generation of drugs for weight control.

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Genes underlie the tendency toward toe tapping,

hair twirling, and other calorie-burning fidgeting.

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What does it mean for a gene to be associated with obesity? Although all human beings share the same basic genetic blueprint, genes that make up that blueprint, or genome, vary from individual to individual. For example, imagine two people, each dressed in the same garments: underwear, pants, socks, shoes, shirt, and so on. If one wears a cashmere sweater and the other a cotton sweater, the one in cashmere will probably be warmer. But not necessarily. What if the cashmere-clad person is caught in an Arctic snowstorm while the cotton wearer visits a Florida beach? In that case, the one in cashmere will feel considerably chillier despite the warm sweater because of the different environment. Similarly, someone who inherits the version of a particular gene that’s associated with obesity will be more likely to wind up fat than someone who inherits a normal version, but that tendency can be affected by environmental factors such as how much fattening food is available. So once researchers have identified the genes of obesity, they must find out how the genes interact with a person’s environment.

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WHEN IT'S NOT YOUR FAULT

By studying what makes mice obese, scientists hope to develop more effective ways for people to fight fat.

With John Wayne bluntness, David West, a geneticist and obesity physician at Parke-Davis in Alameda, California, says, “Some people have the good genes, some people don’t. I think there are some patients, especially the very morbidly obese, who are pretty much a biological problem. They have a real nasty set of genes. As long as they have enough calories to eat, they’re going to be fat no matter what environment they’re in and despite their best efforts.”

Nevertheless, West says most people don’t get fat unless they follow a certain style of life. To gain weight they have to work at it: sit behind a desk all day, wolf down a big lunch, collapse at home in the evening with a few beers, then wake up the next morning and repeat the process. Genes may make them susceptible to weight gain, but a fattening environment makes the gain happen.

In a way, most of us are a lot like a group of mice West has been studying for the past six years. The mice get fat only when they are fed a delectable brand of rat chow that resembles cookie dough—sugar, condensed milk, minerals, and powdered rodent food. As in a typical North American diet, 40 percent of the calories come from fat. And one group of rats in related experiments become obese only when they are offered many different and tasty items simultaneously. Researchers call that a “supermarket” or “cafeteria” diet, and its similarity to the kind of food available to most Americans needs no elaboration.

When West’s mice become fat, they show all the associated biological changes that people do. Their blood sugar goes up, they get more gall-bladder and cardiovascular diseases, and they develop problems with insulin similar to human type II diabetes. Geneticists have shown that this reaction to a rich environment stems from not just one gene but from a multitude of genes that contribute to the animals’ susceptibility, and researchers believe that people have a similar genetic profile.

But just as genes can make us susceptible to obesity, they can also make us resistant. Intriguingly, some strains of mice never become obese despite efforts to fatten them up. Studying these animals may help us understand why some people can eat more than others and never gain weight.

The same idea of genetic resistance and susceptibility applies not only to obesity but also to obesity-related illnesses. West says that “there are a fair number of people walking around out there who are 60, 80 pounds overweight but have normal blood sugar and normal blood pressure. Their joints are fine. They don’t have gallbladder disease. There doesn’t seem to be a greater risk for cancer.

“Why? I think it’s because they have another set of genes that protects them from these adverse effects of being fat.” —S. V.

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The revolution in obesity research began less than five years ago with the landmark discovery of a gene for leptin, the weight-regulating hormone found in both mice and people. Fat mice and skinny mice flashed across TV screens around the world when scientists could finally say that the only difference between them was a single gene. Since then geneticists have uncovered many more weight genes. One, a gene mutation that is also associated with red hair, causes severe obesity. In its normal form, the gene produces a hormone that inhibits eating and also influences hair pigmentation. A mutation in the gene produces a damaged version of the hormone, or no hormone at all. In one case, researchers noticed that both a five-year-old boy and a three-year-old girl who had each inherited two copies of the faulty gene were obese by the age of five months.

News release from the University of Wisconsin
Richard Atkinson
Ways toWin at Weight Loss from the Food and Drug Administration
Obesity web links from the Mining Company