Still hungry? Fattening revelations--and new mysteries--about the hunger hormone.

Too busy to cook, you drop by the neighborhood cafe and treat yourself to fried chicken with a side of macaroni and cheese. You wash it all down with a bottle of apple juice--to balance the high-fat entrees with something healthy. Although you've put away far more calories than usual, you still don't feel really full, so you select a slice of chocolate torte from the dessert case.

Recent studies have begun pointing to a wide variety of factors, including body weight, food choices, and lack of sleep, by which we can unwittingly alter not only when we experience hunger but also what items appear appetizing and how much food it takes to trigger a feeling that we've had enough.

Our bodies rely on a host of involuntary cues to regulate food consumption. In 1999, researchers discovered a hormone that contributes to strong feelings of hunger. Throughout the day, its concentration in our bodies rises and falls. Although we're not aware of these ups and downs, they drive our behavior, either moving us toward the table or letting us get on with the rest of our lives.

Cycles of this powerful hormone--dubbed ghrelin, after a Hindu word for "growth"--reflect a complex interplay of chemical signals that scientists are now beginning to untangle. In the last 2 years, research has also begun pointing to an array of diet and lifestyle factors that modify the body's production of ghrelin and other eating-related signals.

Such findings are not just curiosities. As the complex picture of ghrelin and its allies has been getting clearer, the medical community has begun considering new drugs, lifestyle changes, and other interventions to counter people's penchant for overeating. On the table are billions of dollars and the health of millions of people.

GUT REACTIONS Although many endocrinologists glibly refer to ghrelin as the "hunger hormone," it's got plenty of accomplices when it comes to making people eat--and stop eating--notes Aart Jan van der Lely of Erasmus University in Rotterdam, the Netherlands. Some 2 dozen chemical agents--many of them hormones--stimulate food intake, and a similar number suppress appetite, he says. But only a few of these substances appear to hold feature roles in dinner theater, while the rest serve as understudies or the chorus.

According to recent studies, ghrelin stars as a trigger of appetite (SN: 2/16/02, p. 107). The featured players in appetite suppression include insulin, which is made in the pancreas, and leptin, which fat cells manufacture. These two hormones turn down the dial on ghrelin production. Another appetite suppressor is PYY, a grit hormone that also appears to curb ghrelin manufacture.

All these hormones travel through the body, carrying their eat or don't-eat messages. They also trigger nerve signals running from the gut to the brain and are influenced, in turn, by messages returning from the brain.

As in a great theater production, there's depth in the cast of appetite regulators. When top-billed performers, such as ghrelin, are no-shows, the body turns to understudies to figure out when to eat and, somewhat less effectively, when to stop.

For instance, David E. Cummings of the University of Washington in Seattle and his coworkers reported in the October 2004 Endocrinology that the spike in insulin secretion that occurs after eating usually correlates with a dip in ghrelin production. The researchers found that when they killed rats' insulin-producing cells to model uncontrolled diabetes, food intake still suppressed ghrelin concentrations in the blood, but only about half as effectively as when insulin was present. One or more understudies must take a portion of ghrelin's role, the team concludes.

This study also showed that lack of insulin increased a rodent's sensitivity to ghrelin's call to eat. When Cummings and his coworkers infused a small amount of ghrelin into the diabetic rats, the animals more than tripled their food intake compared with that of healthy rats given the same treatment.

Related studies are homing in on other factors that perturb the normal checks and balances on ghrelin--changes that might keep the hunger bell ringing long after people would otherwise feel full. People may overeat not just when there's a problem with the ghrelin signal but also when something goes amiss in other parts of the control system.

With this new conceptual framework, scientists are looking for means to confront what many have characterized as a worldwide epidemic of obesity (http://www.sciencenews.org/articles/ 20020803/food.asp).

ALL CALORIES AREN'T ALIKE Although most health guides recommend that we eat less fat, people have a hard time complying. The late Walter Mertz, when he was head of the Department of Agriculture's Human Nutrition Research Center in Beltsville, Md., used to sympathize: "The trouble with fat is that it tastes so good."

Cummings' new research points to a related problem: Calorie for calorie, fat is less effective than other nutrients at suppressing ghrelin's hunger call. During one recent study, his team on different days infused into rats' gastrointestinal tracts equal-calorie quantities of pure sugar, protein, or fat. In the February Endocrinology, the group reports that sugar and protein each prompted a rapid, 70-percent drop in the concentration of ghrelin circulating in the rodents' blood. When rats instead received fat, ghrelin concentrations fell far more slowly and by only about 50 percent.

"We've now found the same thing with humans," Cummings told Science News.

These results are consistent with earlier work by his team. For example, the researchers observed in 2003 that prebreakfast, or background, ghrelin concentrations rise as most people lose weight--as if the body is attempting to regain the pounds. However, when people trimmed their waistlines over several months via a low-fat diet, their prebreakfast ghrelin levels remained unchanged.

This "leads us to hypothesize," Cummings says, "that one of the mechanisms behind weight gain typically associated with high-fat diets is that they don't suppress the hunger hormone as well [as low-fat fare does]."

When it comes to sugars, different types can have different effects on ghrelin. For example, Peter J. Havel of the University of California, Davis and his coworkers gave 12 women standardized meals served with custom-prepared drinks sweetened with either of the two table sugar components: glucose, the sugar that cells use for energy, or fructose, the primary sugar in fruits and many soft drinks.

The meals silenced participants' ghrelin signals only about half as much on the days when the accompanying drinks had been sweetened with fructose compared with the days of glucose drinks, Havel's group reported in the June 2004 Journal of Clinical Endocrinology & Metabolism (JCE&M).

Even more interesting is what happened after each day of test drinks, when the women were permitted to eat anything from a buffet. The six women who had reported being careful about their food choices before the study chose fattier fare on the day after imbibing fructose drinks than they did on the day after drinking glucose-sweetened beverages. Moreover, these diners described themselves as being hungrier before meals on the day after getting fructose-sweetened drinks.

The sugar consumed the previous day didn't influence food choice or appetite of the other six women, Havel's team observed.

Though preliminary, these data suggest that even though fewer calories of fructose than calories of other sugars are required to sweeten a food, a high-fructose diet might boost calorie consumption in some people by fostering overeating, Havel notes.

WEIGHTY PROBLEMS

One might expect that people with the highest background ghrelin concentrations in their blood would be the hungriest, eat the most, and end up fattest. It's just the opposite. This observation suggests that many people's bodies are misreading or ignoring hunger and satiety signals.

Obese individuals tend to have the lowest background ghrelin production, as if their bodies are encouraging them to fast (SN: 7/6/02, p. 14). Meanwhile, unhealthily lean people, such as those with anorexia nervosa, can have sky-high background ghrelin concentrations.

Ian M. Chapman of the University of Adelaide in Australia is examining elderly individuals who are healthy except for their poor appetites and inordinately lean physiques. People with this "anorexia of aging" tend to produce twice as much ghrelin as do well-nourished seniors yet claim that they're never hungry, he says.

A similarly perplexing trend appears among 30 non-diabetic but overweight adults whom Arline D. Salbe has studied at a National Institutes of Health center in Phoenix. After being on a weight-maintenance diet for 3 days, the recruits got to eat all they wanted, whenever they wanted, for another 3 days. Each volunteer stayed in a hotel like hospital suite, and dieticians recorded every calorie consumed.

In the June 2004 JCE&M, Salbe's group reported that the higher a volunteer's prebreakfast concentration of ghrelin, the less he or she tended to eat.

Endocrinologist Stephen Bloom of Hammersmith Hospital in London isn't surprised.

Research by Cummings' group last year showed that in normal-weight volunteers, the more calories in a meal, the more it suppressed ghrelin production. But Bloom and his coworkers have found that hunger and satiety signals don't function well in heavy people.

Bloom's team fed 20 normal-weight and 20 heavy adults milkshakelike meals packed with anywhere from 250 to 3,000 calories. In the February JCE&M, the London researchers reported that ghrelin concentrations fell with increasing calories only among the normal-weight men and women. In the obese volunteers, the hormone showed the same drop after all meals, regardless of their milkshake's calorie content. The decline was similar to that in normal-weight people eating a meal with 1,000 calories.

In earlier work, Bloom's team had shown that after a meal the satiety-signaling gut hormone PYY rose less in obese volunteers than in people with normal weight (http://www.sciencenews.org/ articles/20030906/food.asp).

"So now, you've got a double whammy," Bloom told Science News. Compared with other people, the obese remain hungry longer and don't feel full as quickly. "No wonder these poor people can't lose weight," he adds.

HUNGRY FOR SLEEP Since the mid-1960s, the rate of obesity in the United States has nearly tripled to one in three adults. Over the same period, U.S. citizens have deducted, on average, about 2 hours from their nightly slumber. Is there a connection?

Endocrinologist Eve Van Cauter strongly suspects that there is. She points to seven studies that have linked body weight to how long people sleep.

In her lab at the University of Chicago, Van Cauter has also been showing that blood concentrations of hunger and satiety hormones--as well as food preferences--depend on how well-rested people are. For instance, in the November 2004 JCE&M, her research team reported that prebreakfast concentrations of the satiety hormone leptin were roughly 20 percent lower in 11 healthy men who had slept only 4 hours a night for nearly a week than when they had slept 9 hours nightly.

In the December 2004 Annals of Internal Medicine, the researchers reported similar leptin differences in 12 healthy men after just 2 nights of each sleep regimen. Moreover, daytime concentrations of ghrelin climbed 28 percent during the sleep-deprived cycle.

After the second night of sleep deprivation, the recruits' appetites and food intake increased by 24 percent, compared with those after a good night's sleep. Moreover, when sleep deprived, the volunteers chose to consume a larger proportion of their food as high-calorie, carbohydrate-rich items, such as crackers and sweets. Those foods represented 33 to 45 percent more of the calorie intake than they did when the participants were well rested.

Van Cauter has also found that sleep loss increases the activity of the vagus nerve, the trunk line for signals between the gait and the brain. During stress, the brain signals the gut to alter its release of appetite-controlling hormones, which might be the mechanism by which sleep loss changes eating behavior.

People are the only animals to voluntarily ignore their sleep needs, according to Van Cauter. They stay up to play, work, socialize, or watch television. However, she adds, "We're overstepping the boundaries of our biology because we are not wired for sleep deprivation."

HUNGER THERAPY Despite the complexity of appetite control, several large pharmaceutical companies have started developing ghrelin-blocking agents intended to blunt hunger in overweight individuals. Researchers are currently testing these substances on lab animals. From his own work, Cummings notes, ghrelin blockers "look pretty promising."

Currently, Bloom is probing dietary maneuvers to suppress ghrelin peaks and to increase the body's natural production of some of the understudy appetite-quenching hormones. He found that when he injected PYY into people, it suppressed appetite by 30 percent.

The stomach hormone called oxyntomodulin also reduces ghrelin concentration and appetite in people. Indeed, "if we give a fair amount of oxyntomodulin to animals, they don't eat at all," Bloom notes.

In its search for appetite suppressors, van der Lely's team is focusing strictly on ghrelin, which comes in two forms. The type generally described as active is bound to a fatty acid and is called the acylated form. Although the unacylated form "used to be called inactive," van der Lely says, his team has found evidence that it has its own role in eating behavior.

In the February JCE&M, van der Lely and an international group of researchers report that unacylated ghrelin acts as a spoiler to the acylated form. "We have observed that if you experimentally co-administer both [ghrelins]--one in the left arm, and the other in the right arm of people--the unacylated ghrelin can completely abolish all of the effects of the other ghrelin on metabolism," he says. The finding suggests yet another means to silence the call to eat.

Ghrelin is emerging as a hunger hormone with multiple personalities.