UW researchers created a mouse that can eat fat and still lose weight, but can the results be transferred to humans?
Far and wide, people put down their carrot and celery sticks. Folks at Jenny Craig, Weight Watchers, NutriSystem, Diet Center and eat-nothing-but-pineapple-and-blue-algae meetings stuck their heads up like meerkats. Earthshaking news was out and you could just taste the excitement.
Even those folks who didn’t stuff themselves with fen-phen or UltraSlim Fast had to pay attention to this.
A little mouse living in a cage in the K-Wing of the University of Washington’s Warren G. Magnuson Health Sciences Center had done the equivalent of man walking on the moon: he had eaten a high-fat diet—and lost weight. What caught everyone’s attention was that this little fellow was genetically designed by UW researchers. In other words, science made a living, breathing creature who could chug Ding Dongs and not get fat.
Everyone just had to know: could they do that for me?
By the time the year 2005 rolls around, the answer may be yes.
Despite its rap as being a narcissistic trip, weight control is a huge medical problem in this country. According to the National Institutes of Health, half the people living in the United States are overweight, and one-third are clinically obese (weighing 20 percent more than they should). More than 300,000 people die of obesity-related disorders every year. No wonder we Americans fork over more than $30 billion a year on a smorgasbord of weight-loss endeavors.
This breakthrough—and others in the weight-loss world—are sure to start a feeding frenzy among drug companies to develop a pill that in humans will replicate what the UW researchers did with that little mouse. Only recently the U.S. Food and Drug Administration (FDA) approved the first weight-loss drug in 20 years when it gave the stamp of approval to Redux. (Amphetamine, approved in 1952, was the first FDA-approved weight-loss drug.) Appetite suppressants have been with us even before Richard Simmons, and lately people have been gobbling up Redux and another new drug—fenfluramine hydrochloride, aka fen-phen—in hopes they will make the pounds go poof. Redux is said to create chemical changes in the brain that help combat emotional bingeing. Fen-phen, one of the top 10 fastest-growing prescriptions in 1996 (7.3 million sold last year), raises the level of the brain chemical serotonin, which is supposed to tell the body it is satiated.
Drugs like these—poo-poohed by medical experts for being merely another in a long line of quick fixes—haven’t proven to provide long-term help. They have side effects and can’t be taken for more than 12 weeks at a time, says UW Psychologist Stephen Woods, who specializes in obesity.
This UW research could change weight loss drug programs, but the discovery isn’t remarkable simply because of its practical applications. It ranks up there because we now have a physiological understanding of weight control, something that has eluded humanity for years.
The new research focuses on the signals the body sends to the brain, an idea that was actually first put forth back in the early 1950s. Those signals are generated in relation to the amount of body fat you have, explains Dr. Michael Schwartz, a UW endocrinologist the based at Seattle’s Veterans Administration Medical Center.
“That signal tells the brain whether you need to eat more or less,” he says. “If you deplete your fat stores by going on a diet, the signal will tell your brain you need to eat more. You will, and you will gain weight.”
This theory works off the “set-point” idea, whereby the hypothalamus portion of the brain locks onto a body weight. A signal then feeds the brain with information, telling you how much you need to eat. The cycle begins: what you consume affects your weight, and your weight affects the signal telling your brain how much to eat. If you reduce your weight, the signal will tell your brain you need to eat more. Current weight-loss schemes—commercial programs, drugs, hypnosis—try to reduce your weight. But if you do that, signals inside you go haywire, and tell you to eat more. This is the biological reason all commercial weight loss programs fail, according to Dr. John Brunzell, a UW medicine professor.
“There is no fooling the set point,” Schwartz adds. “If you start starving your body, you are messing with the equation of how weight is maintained. If calories are cut back, your brain is going to notice and tell you to start eating more. A diet like that throws all this out of whack.”
Back to the mice. What made the UW research breakthrough particularly exciting was the fact that human beings possess an equivalent of the mouse’s “fat” gene. This was the gene altered in lab mice by the research team of Pharmacology Professor G. Stanley McKnight. The gene caused the extra food eaten by the mouse to be disposed as body heat instead of storing it as fat. Though the gene in people can’t be eliminated or tinkered with, the possibility exists that the same resistance to dietary fat could be achieved through drugs.
Such a substance would have to be available in oral form, and have no side effects to be medically useful, a prospect McKnight says is definitely within reach in the next 10 years or so. With such a large market out there, you can bet drug companies hungry for profits will engage in a dog-eat-dog competition to develop the wonder drug.
In the meantime, the research continues into biochemical reactions in “brown fat,” a kind of tissue that produces heat when an animal is chilled. In people, brown fat is plentiful in infancy but little survives past the age of five. “White fat” makes up the significant portion of body fat, but doesn’t produce heat.
When scientists removed the “fat” gene and created a defect, it turned up the activity of the animals’ brown fat. That, in turn, diverted some of every meal’s nutrients away from white fat, where it would normally have been deposited, to brown fat, where it was burned off immediately.
The effects were astonishing: The mutant mice were lean, with six percent body fat, despite being fed a 58-percent-fat diet. They were warm, with body temperatures 1.5 degrees Fahrenheit higher than normal. They were hungry, and ate more than their normal rodent colleagues. Their metabolism, according to Steve A. Thomas, a UW biochemistry and genetics fellow, was 25 percent higher than normal. “That baffled us,” Thomas says. “We expected these mice to get fat.” Moreover, McKnight says they were quite healthy, fertile and able to get around their cage like their normal brothers and sisters.
Normal mice with the same high-fat diet became obese, their livers clogged with fat, an abnormality associated with overeating. Most became diabetic and died shortly thereafter.
By finding success with the physiological and genetic systems of weight control, doctors have apparently found an important inroad to the long-running “genetics vs. environment” debate. In other words, is a person likely to get heavy because his or her folks were or because he or she lives above the Honey Bear Bakery on Green Lake and can’t resist the killer cinnamon rolls?
Genetics are now thought to determine about 90 percent of a person’s weight. Thus, people who struggle to shed excess pounds on a New Year’s diet shouldn’t blame themselves. “It isn’t their fault,” says Brunzell. “It’s in their genes.”
On the other hand, take a jaunt down to the Arizona desert to see the classic example of the role environment plays in the whole enchilada. The Pima Indians lived in the Valley of the Sun long before the arrival of Europeans and Miracle Whip. As classic hunter-gatherers, the Pimas were rugged, lean and strong. But once the U.S. government forced the Pimas onto reservations in the late 1800s, their lives changed forever. They were exposed to a high-fat diet and their lifestyle became sedentary. Now, 90 percent of all Pimas are obese. Their diabetes rate is staggering. While people from other cultures (such as Asia) have suffered increased cancer rates and other health problems after moving to the U.S., nowhere has an entire people been affected the way the Pimas have.
“Their genetics didn’t change,” says Schwartz. “They could have had a genetic predisposition to becoming obese. But this is clearly an environmental factor.”
Just as clear are some changes in the big picture of body weight. Not long ago, obesity was revered as a sign of wealth. Sons were encouraged to marry heavy women because it meant they were well cared for, and came from well-to-do families. In some cultures that still exists.
But in the 1900s, the ideal body type began to get thinner, especially after World War II. The impact was felt primarily on women and somehow, their success in life became linked to how thin they were. No wonder Cindy Crawford and Kate Moss became bigger female role models than Indira Gandhi or Margaret Thatcher. Then there was a fundamental change in an old belief that obesity was an emotional problem that emanated from the bad habits you had as a kid. Now, science is grasping the fact that biology plays a major role in body weight. One easy way to prove this point was the fact that psychologists who treated obese patients had little success. The idea sunk in that it wasn’t the failure of all these psychologists—the psychological model was all wrong.
“Only in the past decade has the U.S. government embraced the idea that genetic makeup plays a key role in weight gain,” says Woods. “Until then it had been thought that people were somehow weak or had emotional problems that lead to weight gain and obesity. The Food and Drug Administration has finally realized the role biology plays. That is a big change.”
One of the biggest breakthroughs was the discovery of the hormone called leptin. Originally identified late in 1994 after an eight-year search by Rockefeller University researchers, leptin is a protein produced by the obesity gene of mice. Animals with defects in both copies of this gene act as if they are in a state of perpetual starvation, unable to reproduce, stay warm, grow normally and restrain their appetites. Thus, they get grossly fat, weighing as much as three times more than normal animals.
While this is exciting news, mutations in those genes don’t seem to be at fault in human obesity. The now-obese, diabetes-wracked Pimas were found to have low leptin levels but most overweight and obese people have high leptin levels. The large fat stores in people seem to be pumping out the hormone normally, which implies that leptin itself won’t work as an obesity cure. Instead, something must be going wrong in obese people’s response to the hormone, although the difficulty doesn’t seem to be in their leptin receptors.
The problem could be that leptin can’t quite make its way from the bloodstream into the brain, Schwartz has found. In any event, strong evidence shows leptin keeps the peptide called neuropeptide Y in check. This peptide is known as the signal that travels to the brain to stimulate appetite and reduce energy expenditure when it is told that a person’s fat stores seem to be decreasing. When leptin is removed, the NPY system goes nuts, the animal will eat nonstop until he reaches obesity. Drug companies are likely to try to come up with an artificial version of leptin for human regulation of the peptide.
Meanwhile, other hormones, such as insulin, are being scrutinized in the very complicated web of biochemical and brain-signaling circuits that transmit signals such as when to stop eating. Scientists say finding the magic hormone and turning it into a pill to fool your brain could provide one solution to the problem. But beware: all the biology, biochemistry, genetics and pharmaceuticals in the world may be no match for visual cues (that cheesecake looks scrumptious), senses like smell and taste (that pizza is driving me wild), emotional factors (I’m so angry, where is that pint of Haagen Dazs?) and habits (is it 6 o’clock? Dinnertime!).
In other words, science still has an awful lot to digest.
No matter how superbly your natural body weight control systems work, if you have a bad day at the office, get yelled at by your spouse and decide to cope by downing a quart of Baskin Robbins Jamoca Almond Fudge ice cream, you are going to gain weight.
“You can override your exquisite system at any time,” says Stephen Woods, a UW psychology professor and researcher into the psychological factors behind obesity. “Your body can’t compensate for certain behaviors.”
Though a human’s physiology will actually catch up—and cause you to eat less to compensate for the stress-induced binge of calories—what happens outside of the body has tremendous impact on your physiology and hips.
Until only recently, obesity and overeating was considered a psychological problem. As a kid, you had bad habits or reacted to such things as the smell of pizza, and your lack of will power was what did you in and made your waistline expand.
That, in turn, led to the explosion of commercial weight-loss groups and organizations, touting everything from sensibility to nonsense. Well, guess what. It is nearly the year 2000 and there are still gobs of obese people out there.
“Either psychologists have utterly failed,” Woods says, “or the model was wrong, and this isn’t a psychological problem.”
Though the genetic and biological factors regulating body weight have been established, it doesn’t mean finding artificial controls for them through drugs will solve the trick. “I can override the system cognitively,” Woods says. “You cannot predict the size of a meal, and then there are social situations, senses and everything else. Emotions and behaviors do play a big part. And those who think taking a drug to make them thin are in to learn something.”