A Hungry Hormone

A Hungry Hormone

It may be the stomach's way of shouting to the brain, `Feed me!' Dieting just makes it louder By Josh Fischman

When hunger hits, it may not be your stomach grumbling. It may be your hormones--specifically, the oddly named ghrelin, one of the strongest appetite stimulants known. It's so potent that people injected with it chow down as if there's no tomorrow. And last week researchers suggested that ghrelin, produced in the gut, may be the reason that the more people diet, the hungrier they feel--and the reason why so many dieters fail.

Ghrelin may link the stomach to the brain chemically, letting the stomach say "feed me" when food gets scarce. Last week in the New England Journal of Medicine, researchers noted that when dieters lost 17 percent of their body weight, their levels of ghrelin (pronounced GREL-in) rose by 24 percent. "This may be the way your body tries to fight weight loss, a survival signal that evolved to get us to search for food in times of scarcity," says endocrinologist David Cummings of the University of Washington and the Veterans Affairs Puget Sound Health Care System in Seattle, the lead author. "So that, of course, suggests an antighrelin drug could be used to fight weight."
Cummings is quick to point out that no such drug exists and that " the evidence we have so far is only circumstantial." Other scientists add that hunger is a complex sensation, and past attempts to find a single key have not panned out. Still, the hormone is very tempting.

Not only does dieting raise the level of ghrelin, but shrinking the stomach through surgery actually lowers it--and lowers weight, perhaps by reducing the hunger signal along with the organ size. Cummings and his colleagues looked at five obese patients who had gastric bypasses, operations that shrink the stomach so less food gets absorbed. Their ghrelin levels plummeted by more than 70 percent. "These people lose a lot of weight, and we've often thought the reason can't just be mechanical," says Philip Schauer, a surgeon at the University of Pittsburgh Medical Center and a gastric-bypass expert. "Sure, the area that holds food gets smaller, but that shouldn't stop between-meal snacking and slurping milkshakes. Our patients say they have a much-reduced appetite."

Hampering hunger. The last appetite hormone to weigh in with big promises was leptin, in 1995, and it has yet to yield a diet drug. But ghrelin may have more to offer. "It makes you hungry, in theory, so you'd need to block it, and it's relatively easy to find compounds that block," says endocrinologist Eleftheria Maratos-Flier of the Joslin Diabetes Center in Boston. "With leptin, we never really understood the physiology that well."

But weight loss is a tricky business, and researchers have been disappointed by other substances besides leptin. Last year a big drug company developed a potent appetite-inhibitor. The trouble was that each dose created even more-potent erections, sort of a Viagra-plus, seriously limiting the daily drug's usefulness for weight control.

"You don't want to focus on one thing and say, `This is it,' " cautions Maratos-Flier. "There's leptin, there's ghrelin, and above the neck, in the brain, there are several other substances that affect appetite." And the gastric bypass patients had their stomachs physically rewired, so what happens to them could be very different in people without drastic plumbing changes.

Cummings agrees. "If we end up with anything, it may be a kind of cocktail. Look, hunger is important in our evolution. We have many backup mechanisms to keep us from starving, and we may need to deal with all of them. But that is possible to do." By analogy, he notes that blood pressure is also essential to survival, and the body has many strategies--faster heartbeat, slow kidneys, increased thirst--that it uses to keep pressure from falling. But for the millions of Americans whose blood pressure is dangerously high, there are ways of tinkering with these different systems to keep pressure down. It's this kind of multipronged approach, applied to appetite, that Cummings is hungry to try.

AN APPETIZING ASSORTMENT
The body produces a variety of substances that make us feel hungry or make us feel full. Here are some of the major ones:
LEPTIN. A protein made by fat cells appears to produce a full sensation. But overweight people resist its effects.
GHRELIN. Made in the stomach, the hormone's levels drop as people eat and rise when they don't.
OREXINS. These proteins stimulate neurons in the hypothalamus, a brain region that influences appetite.
NEUROPEPTIDE Y. A brain protein, it stimulates feeding, at least in rodents. Leptin may work by disrupting it.

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