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.
Genes underlie the tendency toward toe tapping,
hair twirling, and other calorie-burning fidgeting.
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.
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.
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 WisconsinRichard AtkinsonWays toWin at Weight Loss from the Food and Drug AdministrationObesity web links from the Mining Company
Another newly discovered family of genes makes compounds called uncoupling proteins, which allow people to convert excess fat into heat instead of storing it. Researchers have shown that animals with high levels of these proteins do not gain weight as easily as those with lower levels.
People with the same weight, height, and basic shape
may burn dramtaically different amounts of energy.
Each obesity-related gene affects a different aspect of weight control. For example, one gene might determine how quickly the gut lets the brain know that it is full. Another might dictate how effectively the body turns extra calories into body fat. There’s a genetic component to how much fuel muscles need just to get through a sedentary day. And genes also lie behind a tendency that some people have toward spontaneous physical activity—fidgeting, toe tapping, hair twirling—which burns up a substantial number of calories.
WHY DIETS DON'T WORK
Despite the role genes play in making people fat against their will, diet and exercise remain significant factors. As any dieter knows, losing pounds is never easy. That’s because the body uses a remarkably efficient set of tricks to keep fat at a stable level. Researchers refer to this stable level as the set point. When people successfully lose weight, their bodies undergo a change in metabolic rate that may seem counterintuitive. For example, participants in one study who held their weight at 10 percent below their set point showed a 15 percent drop in daily energy expenditure. Their bodies slowed down energy use to counteract the pounds they had lost. Researchers find this shift in metabolism to be just as marked after a weight gain too. In the same study, subjects who increased their weight showed 10 to 15 percent increases in metabolism.
So if our bodies are so good at maintaining a set point, why do people get fat at all? William Ira Bennett, a doctor at Cambridge Hospital in Massachusetts, recently wrote in the New England Journal of Medicine that although our bodies continue to defend their set points, external factors, such as habitual levels of physical activity and the composition and tastiness of diets, can reset them. Bennett believes that over time a sedentary life and the mere availability of rich, palatable food will slowly increase the weight the body is geared to defend. Because of genes, some people are more susceptible to a change in set point than others. They will always have more trouble keeping off any weight they lose through dieting. —S. V.
It is now widely accepted among weight researchers that a person’s particular complement of genes determines what activities make him or her susceptible to weight gain as well as how strong that susceptibility is. The bottom line is that genes alone don’t make people fat. All of us simply have a greater or lesser genetic tendency to gain weight. Those with the strongest tendency—the worst combination of genes—are almost guaranteed to join the minority of people who weigh 300 pounds and up. The rest lie somewhere on a continuum that extends all the way down to those lucky people who can eat all the doughnuts they want and never need to punch a new hole in their belts.
What’s more, even if two people seem to have roughly the same tendency to gain weight, they may do so for different reasons, simply because of genetic variety. In 14 years of work at the National Institute of Diabetes and Digestive and Kidney Diseases in Phoenix, obesity researcher Eric Ravussin (now at Eli Lilly in Indianapolis) recently uncovered some fascinating examples. He looked at the differences in how people burn energy and how those differences contribute to weight gain. The work made him appreciate how widely metabolic rates can vary.
In a study of more than 500 volunteers, Ravussin and his colleague Pietro Tataranni analyzed resting metabolic rates—how much energy the body uses when it’s just trying to maintain the status quo. The researchers gathered this information using a clear plastic ventilated hood that looks like something out of a viral-scare movie. It fits snugly around a subject’s neck, continuously drawing in and siphoning off air. The wearer must lie awake for 40 minutes without moving. By measuring how much oxygen he consumes and how much carbon dioxide he breathes out, researchers can determine how much energy the subject spends on such basic functions as temperature control and involuntary muscle activity. Ravussin and Tataranni found that some of their volunteers burned as few as 1,067 calories a day, while others burned as many as 3,015.
A woman performs water aerobics at a North Carolina diet and fitness center. While most weight-loss programs involve exercise, its effectiveness can vary dramatically from person to person.
Contrary to what many people think, Ravussin says, a slow metabolism doesn’t necessarily go hand in hand with weight gain. “Most obese patients will tell you, ‘I have something wrong with my metabolism,’” he says. “And I believe that something is wrong. But it may not be their metabolic rate.” When Ravussin has measured rates, he has found that people with the same physical characteristics—same weight, same height, same basic shape—may nevertheless burn dramatically different amounts of energy each day.
Other researchers have shown that exercise has remarkably different effects on different people. When people exercise regularly for three to four months, their bodies can change dramatically: their hearts and muscles get stronger, and they can exercise harder for longer periods. But that is not true for everyone. When exercise physiologist Claude Bouchard of Laval University in Sainte-Foy, Quebec, put a group of 47 young men on a training program for 15 to 20 weeks, he found that some showed 100 percent improvement in their maximal oxygen uptake—a measure of how efficiently lungs, heart, and circulation can dispense oxygen to tissues crying out for it. Other men, however, showed almost no change. Bouchard has seen the same lack of effect on other measurements of how people adapt to exercise, such as heart size, muscle fiber size, and how much work people can perform in 90 minutes. “We believe that it is quite remarkable,” he says, “that for all the determinants that have been considered in a series of investigations performed in our laboratory, one can find nonresponders—even after 20 weeks of regular exercise at a frequency of five times a week over the last several weeks of the program.”
When it comes to weight, it has long been our habit to group heavy people together as if they all suffer from the same condition and should respond to the same cure. Every diet-and-exercise program is pitched as a one-size-fits-all remedy. As scientists begin to understand how different bodies control weight, they are learning to characterize various types of obesity and treat people accordingly. To many researchers and pharmaceutical companies, that treatment means drugs. By one recent count, 62 new compounds for treating obesity are currently in various stages of testing and development. “I expect we’ll see something like one or two new drugs being submitted to us every year for the next five to ten years,” says Leo Lutwak, a medical officer with the FDA’s Center for Drug Evaluation and Research.
CAN A VIRUS MAKE YOU FAT?
Biologists have found a virus that causes obesity in laboratory animals, such as chickens and mice. Now the researchers are testing people for it.
Although the idea sounds more like the premise of a B movie than scientific theory, two scientists at the University of Wisconsin in Madison believe they’ve found a virus that causes some people to get fat. Nikhil Dhurandhar and Richard Atkinson reported recently that when they injected a virus known as AD36 into mice and chickens, the animals’ body fat increased. Because humans were unlikely to volunteer for such experimentation, the scientists decided to test for the presence of antibodies to the virus. Of 154 people tested, about 15 percent of those who were obese had the antibodies. None of the lean people did.
However, the findings don’t necessarily prove that the virus caused obesity in the test group. As several virologists have pointed out, obese people may simply be more susceptible to such a virus. Still, in recent years researchers have been surprised to find that viruses can be linked to so many diseases that had been thought to have other origins. For example, viruses are now implicated in several types of cancer, hardening of the arteries, and even mental disorders such as depression. In addition, five viruses besides AD36 have already been shown to cause obesity in animals. The good news is that the same methods that produce flu shots each year could ultimately be used to create an antiobesity injection. —S. V.
These include the family of so-called exercise pills, drugs designed to boost the rate at which bodies burn fat and dissipate the energy as heat—an effect that would provide many of the benefits of regular mild exercise. Other pharmaceutical approaches use leptin and related molecules to tell the body that its fat stores are already ample, or target the chemicals in our brains that control appetite. Other pills prevent our bodies from absorbing some of the fat that we eat.
But even without new drugs, knowledge of the differences between bodies can lead to more thoughtful ways of dealing with weight. For example, some people tend to have less fat than most of us. As a result, when these people are exposed to a high-fat diet, they gain weight more readily. For them, cutting down on fatty foods might be a far easier and more effective way to maintain weight than, say, embarking on a vigorous exercise program. Ultimately we will be forced to accept that each person’s weight is as much a mark of his individuality as his face. And that could make weight really interesting.