By Sandi Doughton
Seattle Times staff reporter
HARLEY SOLTES / THE SEATTLE TIMES
----------

Rebecca Hildreth started dieting in the fourth grade. Now 29, the Woodinville woman can't recall a day when she wasn't starving herself — or feeling guilty for eating. She has lost weight at least 20 times, and gained it all back.

"It's just a horrible feeling," said Hildreth, who stands 5-foot-5 and weighs more than 300 pounds. "It's worse than anything else in the world."

Like most overweight people, she blames herself for lacking the willpower to stay slim.

"Isn't that what people think?" she asked. "They view you as lazy and undisciplined."

Scientists in the burgeoning field of obesity research don't see it that way.

There's now irrefutable evidence that body weight is largely a function of genes — as much so as height or a family propensity for breast cancer. Those genes are the blueprint for an intricate web of brain chemicals and hormones that regulate appetite and metabolism. In people prone to obesity, new studies show, the system is geared to pack on pounds with exquisite ease while making it devilishly difficult to shed weight.

The findings help explain why diets almost always fail and why gastric bypass and other stomach-reduction surgeries are currently the only way most seriously obese people can slim down permanently.

Drug companies are scrambling to translate recent discoveries into anti-obesity drugs, and experts predict a new generation of medicines will hit the market in five to 10 years.

In the meantime, researchers say, people struggling with their weight — and society's scorn — should take some comfort from the new understanding of why some people get fat and others stay thin.

"Obesity is not a personal failing," said Jeffrey Friedman, a leading geneticist at Rockefeller University in New York City. "Some people are predisposed to become obese and some are not."

Genes and lifestyle

That doesn't mean people can't change their weight through diet and exercise.

Genetics determines the "body-weight ballpark" each person is born into, said endocrinologist David Cummings of the Veterans Affairs Puget Sound Health Care System.

Heavy parents have heavy children, and not just because of lifestyle. Adopted children have body weights more similar to their biological parents than their adoptive parents, Cummings pointed out. Identical twins raised in different households have nearly identical body weights.

"The evidence is very strong that body weight is mostly genetic, with some environmental contributions," he said.

Online resources
･ Jessica and Leo Loos, who both underwent gastric-bypass surgery recently, are chronicling their experience: www.jeleo.com

･ American Society for Bariatric Surgery: www.asbs.org

どのように私は液体overcounterをノックアウト購入することができるでしょうか？

･ Evergreen Morbid Obesity Surgery Support group (EMOSS): www.emoss.info

･ More resources: www.obesityhelp.com At a recent family reunion, Hildreth marveled at the number of overweight relatives. "I finally accepted that I look like them," she said.

People can prevail over their genes — though few succeed in the long term. On a starvation diet, even a person with the genes of a 400-pounder will be gaunt. Under more ordinary conditions, most people can shave no more than 5 to 10 percent off their "natural" body weight by exercising and eating wisely, Cummings said.

Decades of diet studies show that more than nine out of 10 people who lose weight by dieting gain it all back within five years.

"There are exceptions, but when you are speaking of general rules, the only people who are able to lose more than 10 percent of their body weight and keep it off are people who have had gastric-bypass or other bariatric surgery," Cummings said.

Jessica and Leo Loos of Sammamish both opted for the surgery in January after trying dozens of diets, eating plans and exercise programs. (The couple's experiences were chronicled in Sunday's Seattle Times.) Jessica estimates she has made serious efforts to lose weight 50 times in her 26 years, beginning at the age of 12. Every attempt ended in failure, often with binge eating.

"Once you start gaining weight, it's a lot easier to keep gaining weight than it is to lose it," she said. "It's habitual, like an addiction."

Loos and Hildreth both invoke emotional failings to explain their diet backsliding: Food fills a void in their lives or offers comfort when they're depressed, they say.

Emotions, social pressures and stress can all contribute to weight problems, said University of Washington researcher Scott Weigle, but those factors are usually not as strong as biology. The overwhelming urge to eat and the body's reluctance to let go of fat are both strongly influenced by genetics, he said.

"If you're not tuned in to the fact that biology is at work here, you're very likely going to blame yourself."

But genetics alone can't explain the explosion of obesity around the globe.

More than 60 percent of American adults are overweight, about half of those obesely so. The number of obese children in France has increased five-fold since 1990. Even nomadic reindeer herders in the Siberian tundra have seen a startling jump in obesity since the Soviets collectivized the herds and fewer people follow the migration.

The human gene pool hasn't changed in a matter of decades, but the human environment has. Cheap, high-calorie foods are increasingly available, and physical activity is declining.

To understand why that combination is a recipe for disaster, scientists look to humanity's distant past.

どのような疾患はmusculrシステムに影響を与えるか？

Our ancestors evolved in a world where food was often scarce and unpredictable. People were more likely to survive if they were good at gobbling food and accumulating fat stores to see them through the next famine.

Today, food is plentiful in much of the world, and it doesn't take hard work to get it.

But our bodies haven't adapted. Mechanisms that evolved millions of years ago to prevent starvation are still chugging along — only now they're creating an epidemic of life-threatening obesity.

"Genetics made us ready to gain weight when the environment allowed it — and now the environment allows it all the time," Cummings said.

Chemical controls

Over the past few years, researchers have started to unravel the interaction between chemical signals that originate in fat cells and the digestive system and the brain centers where the signals are processed and converted into feelings of hunger or fullness.

In about a third of people, those systems are genetically geared to maintain a fairly normal, lifelong weight, said Dr. Michael Schwartz, an obesity researcher at the UW and Harborview Medical Center. These are the people who never seem to develop a paunch no matter what they eat.

In the rest of us, the systems are stacked to favor weight gain and thwart weight loss.

The kingpin is a hormone called leptin. Produced by fat cells, leptin is the way the brain keeps track of the body's fat stores.

When fat — and leptin — are high, the brain switches into weight-loss mode, inhibiting appetite and speeding up metabolism, the rate at which the body burns calories.

When fat stores and leptin levels drop, as during a diet, the brain tries to put the fat back on by boosting appetite and slowing metabolism.

People who lack a normal leptin gene are hugely obese but slim down after leptin injections.

"If you don't have leptin, it's as if the brain is getting the message: There's no fat, and you need to eat more," Schwartz said.

But leptin injections don't help people with ordinary obesity shed pounds, because they become resistant to the hormone.

"Something about gaining weight actually changes your system to make it harder to lose it," Cummings said.

After weight gain, the body re-adjusts its internal fat barometer upward. When fat starts melting away, the body senses the change and hits the panic button, activating multiple systems to replenish the stores — and frustrating dieters.

Another example is ghrelin (pronounced grell-in), a hormone produced in the stomach.

Discovered in 1999, it causes the hunger pangs that strike before meals.

Obese people don't have unusually high ghrelin levels — until they start losing weight. As fat disappears, ghrelin soars, triggering intense hunger and helping explain why it's so hard to stick with a diet, Cummings discovered.

白血病はどのように継承されます。

Ghrelin may also help explain why gastric-bypass surgery is the single most effective method to keep off large amounts of weight.

Ghrelin levels plummet after the surgery, which reduces the stomach to a tiny pouch. That's probably why patients report a dramatic loss of appetite and usually don't compensate for their small stomachs by eating more often, Cummings said. He suspects the effect stems from the fact that the operation routes the digestive system away from the stomach's main ghrelin-producing region.

An alphabet soup of other compounds also plays roles in regulating appetite and weight:

･ CCK, produced in the gut, signals the brain when the stomach is full.

･ A hormone called GLP-1 is responsible for the queasy feeling that comes with overeating.

･ From the colon comes a chemical called PYY that sends the message that it's time to stop eating.

Recent experiments in Oregon found that people who got injections of PYY ate a third less than usual — and reported no appetite for 24 hours.

Results such as those are fueling pharmaceutical companies' frenzied quest for anti-obesity drugs and the profits they would reap.

"Can you imagine anything that would make a drug company more money?" Cummings asked.

Much of the drug-related research is focusing on the hypothalamus, the portion of the brain that seems to be the body's master weight-control center. Leptin, ghrelin and other hormones act directly on this region, activating weight-loss or weight-gain neurons that in turn release a cascade of brain chemicals, some of which are promising drug targets.

But tinkering with one of man's most fundamental drives is a major challenge, Schwartz said. Scientists might develop a drug that blocks one weight-gain pathway, only to see its benefits erased when another pathway kicks in to compensate.

He predicts the first new drugs could reach the market within five years but cautions against expecting a single pill that melts away pounds. More likely are drugs people take after losing weight to prevent the fat from coming back.

Blame or biology?

But why can't more people be like Chele Franz, who lost 100 pounds and has kept it off for more than a decade without diet drugs or surgery?

The 47-year-old Lake Forest Park woman topped out at 260 pounds in the seventh grade. She vowed she wouldn't be fat when she entered high school, and with a few episodes of backsliding, has maintained her weight around 160 ever since.

Stories such as Franz's are one reason society blames overweight people for their own plight, said Friedman, the Rockefeller University geneticist.

"You can't say it's impossible for people to lose enormous amounts of weight and keep it off, because we all know people who have done it."

Few people realize how difficult it is. "It's a constant, constant struggle," said Franz, who has to work out at least an hour every day and be endlessly vigilant about what she eats. "I consider losing weight as tough as an alcoholic or drug addict kicking the habit."

Most people simply can't do it, and it's not because they're slothful, Friedman said.

"People who are heavy don't exercise less willpower than the average person. If anything, lean people don't have to exercise the willpower that heavy people do."

The genetic and biochemical systems that regulate body weight are, for the most part, as unconscious — and uncontrollable — as heart rate or body temperature.

People can control how much they eat — but only to a point.

"Most of us say, 'How much I eat is up to me,' " Schwartz said. "That's true, but if you're hungry all the time, you're going to eat more."

That doesn't mean people who are obese should simply wait for new drugs to solve their problem, he said. It's possible for almost everyone to lose at least some weight with diet and exercise, and even a small weight loss can have big health benefits.

People who aren't obese, but who are watching their waistlines expand, should also heed the new research, Schwartz said. Obesity sneaks up gradually on most people — a few pounds a year, until 20 years have passed and they're 50 pounds overweight.

Minor changes in diet and physical activity may be sufficient to stem that creep.

"I think the exercise component is critical," Schwartz said. "If people exercised, that would probably give them some protection against obesity."

With studies revealing how fiercely the body resists weight loss once the fat has settled in, Schwartz said, it's clear that protecting against weight gain in the first place is the best hope for stemming the obesity epidemic.