Science / Medicine : Hunger : It’s All in Your Head : Biology: The urge to eat is triggered by powerful hormones acting in the brain, studies of animals reveal. The finding should lead to radical new ways of treating obesity and eating disorders. Appetite control would replace dieting.
As anyone who has ever tried to diet knows, hunger is one of the most powerful human desires. The urge to eat is so strong that one in four Americans is more than 20% overweight, impairing their health and, in many cases, shortening their lives.
Some view this powerful urge as a defect in character, a wimpish inability to take control of one’s own destiny. Others see it as a “genetic fossil,” a lingering vestige of prehistoric eras when a few extra pounds could ensure survival during a period of famine.
The truth apparently is somewhat simpler. A growing body of evidence suggests that hunger is caused by a very small number of chemicals in the brain, particularly a hormone called neuropeptide Y or NPY.
Studies in a wide variety of animals over the past few years indicate that when NPY is present in a critical area of the brain, the animal will eat. If it is present in high quantities, the animal will eat until it is no longer physically capable of holding more food. And if NPY is not present, or its action is blocked, the animal will lose its appetite.
It now seems likely that in the vast majority of cases, obesity may be caused by simple overproduction of NPY. The binge-and-purge cycles of bulimia may also be the result of faulty production of NPY, and the starvation of anorexia nervosa may be the product of faulty cellular responses to it. Even the overeating caused by such disorders as diabetes may be directly linked to irregularities in NPY production or utilization.
The discovery of NPY’s role in the regulation of weight has “profound clinical implications,” according to psychologist B. Glenn Stanley of UC Riverside. It opens the door to the development of agents that will block its appetite-stimulating activity, thereby perhaps making it much easier for the obese to lose weight. It may also be possible to develop drugs that will stimulate its activity, which would be of benefit not only to anorexics, but also to people suffering from cancer and other diseases in which appetite loss leads to wasting.
But because of the chemical’s complexity, that development is likely to take time. NPY has a variety of functions throughout the brain, and drugs that inhibit its actions too broadly may have a variety of undesirable side effects.
Amphetamines, for example, suppress NPY activity, which explains their earlier use in weight control, but they have too many other effects on the brain to be safely used for that purpose. An anti-obesity drug will have to be highly targeted. Nonetheless, Stanley believes such drugs will be available “within a decade.”
The effect of NPY on appetite was discovered independently in 1984 by two teams of researchers: Jack Clark, who was working in the laboratory of gynecologists Satya Kalra and Pushpa Kalra at the University of Florida College of Medicine in Gainesville; and Stanley, who was then working in the laboratory of neurobiologist Sarah Leibowitz of Rockefeller University in New York City.
When he first injected NPY into the brain of a rat and saw it begin to eat, “That was the single best day of my life,” Stanley said. In most experiments in science, the effects are subtle and often hard to discern, he explained. “It’s an indescribable feeling . . . to get an overwhelming effect in a first experiment and know it’s important.”
What Stanley observed was that rats began eating within 20 minutes after NPY was injected into a particular area of their brains, called the paraventricular nucleus of the hypothalamus, and they demonstrated an “eating behavior of unparalleled proportions.”
Even if they had just finished a normal meal, the rats would resume eating and continue until they could hold no more food. The effect was independent of all external stimuli that normally affect feeding, such as time of day. If the animals had not eaten, NPY would cause them to eat in an hour what they would normally eat in a day and they would continue overeating for several hours afterward.
Remarkably, injections of the hormone directly into the hypothalamus--which is known to be involved in regulating eating behavior--seems to produce few other observable effects, except for an increased consumption of liquids. And unlike the case with drugs of abuse, or even with many pharmaceuticals, the animals never develop any tolerance for NPY. It provides as much stimulus on the hundredth injection as on the first.
Since those initial studies, NPY has been shown to produce identical effects in a wide variety of species, including other rodents, snakes, various birds, pigs and sheep. Researchers have not attempted to demonstrate the effect in humans because NPY has to be injected directly into the brain to be effective and such injections would be unethical, but they are confident that humans are no different from other animals in this respect.
Stanley and Leibowitz also found that NPY is selective in its action. When they injected it into rats and offered them meals containing primarily either fats, proteins, or carbohydrates, they observed that the animals chose carbohydrates almost exclusively. Leibowitz has subsequently discovered that another peptide hormone, called galanin, stimulates desire for fats. Researchers have not yet identified any chemical that works primarily for proteins.
The fact that injected NPY stimulates feeding does not mean that is its normal role. But strong evidence that this is the case was provided last December by the Kalras.
In rats, they surgically implanted thin tubes that led directly to the hypothalamus. Through this tube they could inject a microscopic amount of saline solution and then suck it back out. Analysis of the contents of the retrieved solution would then reveal what hormones were present in that area of the brain.
They found that when the animals were hungry, the concentration of NPY was higher than normal. As they ate and became full, the NPY levels dropped.
“This finding provides the first clue that there is a relationship between appetite and the amount of this peptide that’s released in the brain,” said Satya Kalra. “If you’re hungry, you are going to produce more of the peptide.”
A variety of evidence links NPY to eating disorders. In rats that are genetically obese, for example, researchers have found that they continuously have above-normal concentrations of NPY in their brains and that this high production is genetically controlled. Most researchers believe that the same holds true in humans, but no one has studied it yet.
Unfortunately, no animal models exist for either bulimia or anorexia nervosa, so researchers can study both only in humans. But because they cannot study levels of NPY in human brains, they have to devise indirect measures.
Psychiatrist Walter Kaye and his colleagues at the University of Pittsburgh Medical Center are the only researchers who have studied NPY in humans. They have extracted cerebrospinal fluid (CSF) from more than 100 patients with bulimia and anorexia and monitored NPY concentrations.
Kaye found that the concentration of NPY was unchanged in bulimics, but that the level of a closely related neuropeptide called YY increases in the fluid when the bulimics are entering a binge cycle and returns to normal afterward. Peptide YY has the same effect in the body as NPY, but works at much lower concentrations.
In anorexics, in contrast, Kaye’s results suggest that the problem lies not in production of NPY, but in its uptake by target cells. NPY enters the cells and exerts its effects by binding to specific molecules called receptors. Defects in such receptors are the cause of a variety of diseases, including certain types of diabetes.
When receptors are defective, the body typically responds by producing more of the messenger chemical that binds to it. That is what Kaye has observed in anorexics. He observed that concentrations of NPY were high in cerebrospinal fluid from anorexics, even though they showed little desire to eat. Those levels returned to normal when the anorexics under treatment returned to their normal weight.
Kaye plans to begin measuring NPY levels in cerebrospinal fluid of obese people in the near future to see if concentrations are abnormal, as has been predicted.
If NPY is the cause of obesity, then theoretically a chemical that blocked its action should be a sure-fire weight-control drug. Researchers are looking intensely for such agents, while attempting to prove that blocking NPY will eliminate appetite.
Psychologist Kazumiko Tatemoto, formerly of Stanford University and now at Gunma University in Japan, reported at a meeting two years ago that he had identified some small synthetic peptides that also blocked the activity of NPY. Other researchers, including Stanley, have been unable to reproduce his results.
Recently, Stanley has found that injection of antibodies against NPY (prepared in other animals) into the hypothalamus reduces the animals’ appetite by binding to NPY and preventing it from reaching receptors. The injection blocked appetite even when the animals had been deprived of food. Antibodies against NPY would not be a practical drug, but his results show the approach is promising.
“My guess is that we’ll be able to develop very specific, very potent blockers of the receptors that will reduce hunger and eating,” Stanley concluded. “But it’s still going to take a lot of very hard work.”
