Uncontrollable Causes of Obesity: Leptin

Leptin

By the time they arrived at the hospital at the University of Cambridge in England, the two children were dangerously obese. Rolls of fat encased their bodies, making walking difficult. The eight-year-old girl weighed 190 pounds. Almost 60 percent of her body was made up of fat. Her cousin, a boy of two, already weighed more than 63 pounds. They were ravenously hungry all the time. Nothing the parents or doctors could do kept them from eating -- or from getting fatter.

Then, a kind of miracle. Doctors injected the children with a genetically engineered version of a hormone that controls appetite and metabolism. "Within days their hunger subsided," says Sadaf Farooqi, one of the physicians who treated the kids. "Without any prompting, after two weeks they were eating 90 percent fewer calories." The fat began to melt off. By the end of a year, they were down to a normal weight for children their ages.

Such is the dream of every dieter: a treatment that makes you slim by magically suppressing hunger. In reality, the children treated at Cambridge are among a group of perhaps a dozen around the world with a genetic defect that makes them eat ceaselessly and never feel satisfied. But their extraordinary case points up how far science has come in understanding why some people are thin and others fat, no matter how much they diet. The latest insights into genetics, proteins, hormones -- and a virus -- could soon lead to personalized weight loss and even a shot or a pill to "cure" fatness.

Survival of the Fattest
"Given the world we live in, the real question isn't why people get fat, but why some people manage to stay thin," says Eric Ravussin, a scientist at the Pennington Biomedical Research Center in Baton Rouge, Louisiana.

"People who could take in lots of calories when food was available and store them efficiently in the form of body fat were the people most likely to survive through famines and pass on their genes," says Ravussin. "For millions of years, evolution favored people of this 'thrifty' genetic type." Only now, in an environment of restaurants, grocery stores or quickie food marts on nearly every corner, has it turned into a liability.

Not all of us possess thrifty genes. "Populations that lived as hunter-gatherers were probably more vulnerable to periodic feasts and famines, so evolutionary pressure was more intense to select thrifty genotypes," says Ravussin. Populations that began farming early on stored food for the winter -- an alternative to storing it as body fat. "As they evolved, they may have begun to lose the thrifty genotype."

So while some people really can eat all they want and stay thin, they are evolutionary oddities, not the norm, says Ravussin. Most of us have a genetic profile that leads us to get fat when there's plenty of food.

Popular diet plans have fostered a myth that obesity is due to a lack of willpower. But Jeffrey Friedman of Rockefeller University, a leading researcher in exploring the reasons we get fat, insists that's not true. Says Friedman: "Genes play as big a role in determining how fat we are as they do in determining our height."

The Hunger Switch
Somewhere along the evolutionary ladder, fat cells began communicating with the brain (and the message wasn't "More Twinkies"). The first understanding of this chatter came in 1994, when Friedman discovered a hormone called leptin. "Leptin is part of a complex system that closely regulates body fat and hunger," says Friedman. "When we put on fat, fat cells release leptin, which signals the brain to suppress appetite." What's more, leptin sends a message to crank up metabolism. "When we burn fat, leptin levels fall, and the hunger center of the brain says, 'Eat something.' "

The Cambridge children had a genetic defect that kept their bodies from making leptin. With the discovery of leptin and proof of its dramatic effect on leptin-deficient patients, jubilant scientists thought they had finally found a magic bullet for dieters. But extreme leptin deficiency turns out to be exceedingly rare. Paradoxically, 85 to 90 percent of obese people actually turn out to have higher than normal levels. "The problem isn't that they don't make enough," Friedman explains, "but that they are comparatively insensitive to leptin's effects."

St. Louis University professor William A. Banks recently offered a provocative reason for leptin resistance: The hunger-suppressing hormone may have trouble reaching the brain. In findings reported in March, Banks showed that triglycerides -- fat particles in the blood -- can gum up the blood-brain barrier, making it hard for leptin to get across. "As people gain weight, levels of triglycerides rise, which may prevent leptin from reaching the brain," explains Banks, who conducts his research at the VA Medical Center in St. Louis. "People are hungry and eat more, adding even more fat."

Whether triglycerides or another factor blocks leptin, once people become overweight, resistance to the hormone makes it harder to lose pounds. People who are resistant need more leptin to suppress appetite. But as fat cells shrink, levels of the hormone fall. That drop-off triggers hunger pangs and slows down metabolism. The brain responds as if to a famine, conserving energy and ordering you to eat, eat, eat. With each pound of fat lost, shedding weight and keeping it off becomes more difficult.

Anti-Fat Pharmaceuticals

The findings show why so many people who lose weight will gain it back again. But they also offer hope. By zeroing in on the biochemical pathways that control hunger and satiety, scientists are already coming up with promising new ways to fight obesity. Researchers at Rockefeller University are currently testing whether giving leptin to people who have lost significant amounts of weight will help them keep the weight off. Other biochemicals may also yield fat-busting drugs. Friedman recently announced the discovery of an enzyme called SCD-1 -- controlled by leptin -- which the body needs to build fat cells. When researchers at the University of Wisconsin deleted the gene that makes SCD-1 from mice, the animals were able to feast on high-fat meals without gaining weight.

The Fat Virus
While some researchers search for the roots of obesity in our genes, others investigate infections. Scientists have known for two decades that, surprisingly, certain viruses can cause birds or mammals to become fat. Now Nikhil V. Dhurandhar, a nutritional biochemist at Wayne State University in Detroit, thinks he's tracked down a bug that can cause obesity in people.

The alleged culprit is human adenovirus-36, or AD-36. In a study published in 2002, Dhurandhar showed that AD-36 injected into monkeys causes dramatic weight gain. In some animals the virus caused body fat to triple. It's unethical to inoculate people with the virus, of course. But in an analysis of 1,000 people, Dhurandhar and his colleagues found that those with AD-36 antibodies -- a sign that they've been infected -- are significantly more likely to be overweight.

How could a virus make you fat? When fat cells are exposed to AD-36, Dhurandhar has found, they begin to multiply. "I'm not saying all obesity is caused by a virus. Genes, metabolism, habits all play a role," he acknowledges. "But at least one other possibility appears to be infection."

As yet, no one knows how widespread AD-36 may be, or how big a role it might play in the current obesity epidemic. If Dhurandhar's suspicions prove correct, the next step would be developing a vaccine.

The Fidget Gene
Assuming you're not carrying an exotic virus, your weight will be determined -- in part -- by how much you eat. Equally important is how much you move, and here, too, researchers are learning that genes play a powerful role. Scientist Eric Ravussin has found that basal metabolic rate -- the number of calories we burn just to keep all basic systems running -- varies among individuals by as much as 500 calories a day. A low or high metabolism runs in families, proving that it is genetically controlled.

Ravussin's experiments turned up another trait that determines how fast we burn calories: fidgeting. "Some people jiggle their legs, tap their fingers, and otherwise fidget more than others," says Ravussin. The tendency runs in families. In a recent study at the Mayo Clinic's Endocrine Research Unit in Minnesota, physician James Levine fed 16 people an extra 1,000 calories a day. After two months, the natural fidgeters in the group weighed the same; those who barely moved had gained 12 pounds.

Levine found that the fidgeters were more sensitive to calories. "They unconsciously increase their activity level after they eat too much," Levine explains. Researchers have identified a protein that, when injected into animals, turns on fidgeting. Says Levine: "Give rats a shot of this protein and they start zipping around the cage. When they stop getting injections, they get slow and lazy again." Scientists have already tested several metabolism-boosting substances in humans, including dinitrophenol and thyroid hormone. Unfortunately, both have potentially dangerous side effects, so they can't be used as drugs. Still, the researchers are confident they're nearing a breakthrough.

Changing the World
"We can't ignore genes," says Steven Heymsfield, who studies metabolism and obesity at St. Luke's-Roosevelt Hospital Center in New York. "But we can't ignore environment either."

And environment is something we can change. "We choose the world we live in, after all, both individually and collectively," says Charles Billington, associate director of the Obesity Research Center at the University of Minnesota. "It's up to us to decide what we eat and don't eat. It's up to us to decide whether to watch an hour of television or go for a walk. We're shaped by our genes. But we're not their victims."

Now that some members of the food industry have begun to reduce portion sizes and raise nutritional awareness among customers, future generations may be able to reverse the disturbing weight trends we're facing. But as we grapple with change, the latest genetic findings offer hope to the overweight and obese. "Patients used to blame being overweight on glands and hormones, and we doctors would say, 'It's not hormones, it's calories,' " says Banks. "Now we know hormones are involved."

And the hunger cues those hormones stimulate may be so strong in many people that even the steeliest willpower isn't enough to resist them. Friedman, whose discovery of leptin jump-started research into anti-fat pharmaceuticals, says it's unrealistic and unfair to expect severely obese people to use sheer willpower to fight the powerful genetic forces that drive them to put on pounds. "People can diet and lose 10 or 15 pounds. But real obesity isn't a willpower problem. It's a medical problem."