Still Hungry?
Fattening revelations—and new mysteries—about the hunger hormone
Janet Raloff
Too busy to cook, you drop by the neighborhood café 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.
Dean MacAdam
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: http://www.sciencenews.org/articles/20020216/bob10.asp). 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 gut hormone that also appears to curb ghrelin manufacture.
D. MacAdam
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 (see Surprise!
Obesity (and Inactivity) Can Spur Cancers) (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."
D. MacAdam
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: Available to
subscribers at http://www.sciencenews.org/articles/20020706/note16.asp). Meanwhile, unhealthily lean people, such as those with anorexia nervosa, can have sky-
high background ghrelin concentrations.
D. MacAdam
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
(see A New Shot at Fighting Obesity).
"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?
D. MacAdam
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 caloric 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 gut 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.
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References:
Batterham, R.L. . . . and S.R. Bloom. 2003. Inhibition of food intake in obese subjects by peptide YY3–36. New England Journal of Medicine 349(Sept. 4):941-948. Available at http://content.nejm.org/cgi/content/full/349/10/941.
Broglio, F. . . . A.J. Van der Lely, et al. 2004. Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. Journal of Clinical Endocrinology & Metabolism 89(June):
3062-3065. Abstract available at http://intl-jcem.endojournals.org/cgi/content/abstract/89/6/3062.
Cohen, M.A. . . . and S.R. Bloom. 2003. Oxyntomodulin suppresses appetite and reduces food intake in humans. Journal of Clinical Endocrinology & Metabolism 88(October):4696-4701. Available at http://intl-jcem.
endojournals.org/cgi/content/full/88/10/4696.
Cummings, D.E., K.E. Foster-Schubert, and J. Overduin. 2005. Ghrelin and energy balance: Focus on current controversies. Current Drug Targets 6(March):153-169. Abstract available at http://www.ingentaconnect.
com/content/ben/cdt/
2005/00000006/00000002/art00003.
Cummings, D.E., et al. 2004. Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. American Journal of Physiology-Endocrinology and Metabolism 287(August):
E297-E304. Abstract available at http://ajpendo.physiology.org/cgi/content/abstract/287/2/E297.
Cummings, D.E., et al. 2001. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50(August):1714-1719. Available at http://diabetes.diabetesjournals.org/cgi/content/full/50/8/1714.
Gauna, C. . . . and A.J. van der Lely. 2005. Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes. Journal of Clinical Endocrinology & Metabolism 90(February):1055-1060. Abstract
available at http://intl-jcem.endojournals.org/cgi/content/abstract/90/2/1055.
Gauna, C. . . . and A.J. van der Lely. 2004. Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unacylated ghrelin strongly improves insulin sensitivity. Journal of Clinical
Endocrinology & Metabolism 89(October):5035-5042. Abstract available at http://intl-jcem.endojournals.org/cgi/content/abstract/89/10/5035.
Gelling, R.W. . . . D.E. Cummings, et al. 2004. Effect of uncontrolled diabetes on plasma ghrelin concentrations and ghrelin-induced feeding. Endocrinology 145(October):4575-4582. Abstract available at http://endo.
endojournals.org/cgi/content/abstract/145/10/4575.
le Roux, C.W. . . . and S.R. Bloom. 2005. Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. Journal of Clinical Endocrinology & Metabolism 90(February):
1068-1071. Abstract available at http://intl-jcem.endojournals.org/cgi/content/abstract/90/2/1068.
Overduin, J. . . . and D.E. Cummings. 2005. Role of the duodenum and macronutrient type in ghrelin regulation. Endocrinology 146(February):845-850. Abstract available at http://endo.endojournals.
org/cgi/content/abstract/146/2/845.
Salbe, A.D., et al. 2004. Negative relationship between fasting plasma ghrelin concentrations and ad libitum food intake. Journal of Clinical Endocrinology & Metabolism 89(June):2951-2956. Abstract available at http://intl-
jcem.endojournals.org/cgi/content/abstract/89/6/2951.
Spiegel, K. . . . and E. Van Cauter. 2004. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Annals of
Internal Medicine 141(Dec. 7):846-850. Abstract available at http://www.annals.org/cgi/content/abstract/141/11/846.
Spiegel, K. . . . and E. Van Cauter. 2004. Leptin levels are dependent on sleep duration: Relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. Journal of Clinical Endocrinology &
Metabolism 89(November):5762-5771. Abstract available at http://intl-jcem.endojournals.org/cgi/content/abstract/89/11/5762.
Sturm, K. . . . and I.M. Chapman. 2003. Appetite, food intake, and plasma concentrations of cholecystokinin, ghrelin, and other gastrointestinal hormones in undernourished older women and well-nourished young and
older women. Journal of Clinical Endocrinology & Metabolism 88(August):3747-3755. Available at http://intl-jcem.endojournals.org/cgi/content/full/88/8/3747.
Teff, K.L. . . . and P.J. Havel. 2004. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. Journal of Clinical Endocrinology &
Metabolism 89(June):2963-2972. Abstract available at http://intl-jcem.endojournals.org/cgi/content/abstract/89/6/2963.
Van der Lely, A.J., et al. 2004. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocrine Reviews 25(June):426-457. Abstract available at http://edrv.endojournals.
org/cgi/content/abstract/25/3/426.
Further Readings:
Batterham, R.L. . . . and S.R. Bloom. 2003. Pancreatic polypeptide reduces appetite and food intake in humans. Journal of Clinical Endocrinology & Metabolism 88(August):3989-3992. Available at http://jcem.endojournals.
org/cgi/reprint/88/8/3989.
Blom, W.A.M. . . . and H.F.J. Hendriks. 2005. Ghrelin response to carbohydrate-enriched breakfast is related to insulin. American Journal of Clinical Nutrition 81(February):367-375. Abstract available at http://www.ajcn.
org/cgi/content/abstract/81/2/367.
Broglio, F. . . . A.J. van der Lely, et al. 2003. Effects of ghrelin on the insulin and glycemic responses to glucose, arginine, or free fatty acids load in humans. Journal of Clinical Endocrinology & Metabolism 88(September):
4268-4272. Available at http://intl-jcem.endojournals.org/cgi/content/full/88/9/4268.
Broglio, F. . . . A.J. van der Lely, et al. 2003. The endocrine response to ghrelin as a function of gender in humans in young and elderly subjects. Journal of Clinical Endocrinology & Metabolism 88(April):1537-1542. Available
at http://intl-jcem.endojournals.org/cgi/content/full/88/4/1537.
Callahan, H.S., D.E. Cummings, et al. 2004. Postprandial suppression of plasma ghrelin level is proportional to ingested caloric load but does not predict intermeal interval in humans. Journal of Clinical Endocrinology &
Metabolism 89(March):1319-1324. Available at http://intl-jcem.endojournals.org/cgi/content/full/89/3/1319.
Christensen, D. 2002. Hunger hormone gone awry? Science News 162(July 6):14. Available to subscribers at http://www.sciencenews.org/articles/20020706/note16.asp.
de Graaf, C., et al. 2004. Biomarkers of satiation and satiety. American Journal of Clinical Nutrition 79(June):946-961. Available at http://www.ajcn.org/cgi/content/full/79/6/946.
Neary, N.M. . . . and S.R. Bloom. 2004. Ghrelin increases energy intake in cancer patients with impaired appetite: Acute, randomized, placebo-controlled trial. Journal of Clinical Endocrinology & Metabolism 89(June):2832-
2836. Abstract available at http://intl-jcem.endojournals.org/cgi/content/abstract/89/6/2832.
Raloff, J. 2002. Surprise! Obesity (and inactivity) can spur cancers. Science News Online (Aug. 3). Available at http://www.sciencenews.org/articles/20020803/food.asp.
Seppa, N. 2001. Weak appetite in elderly ties to hormone. Science News 160(Dec. 22):390. Available to subscribers at http://www.sciencenews.org/articles/20011222/fob6.asp.
Stock, S. . . . S.R. Bloom, et al. 2005. Ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide, and hunger responses to a mixed meal in anorexic, obese and control female adolescents. Journal of Clinical
Endocrinology & Metabolism 90(April):2161-2168. Abstract available at http://jcem.endojournals.org/cgi/content/abstract/90/4/2161.
Taheri, S., et al. 2004. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Medicine 1(December):e62. Available at http://dx.doi.org/10.1371/journal.pmed.0010062.
Tassone, F. . . . A.J. van der Lely, et al. 2003. Neuroendocrine and metabolic effects of acute ghrelin administration in human obesity. Journal of Clinical Endocrinology & Metabolism 88(November):5478-5483. Available at
http://intl-jcem.endojournals.org/cgi/content/full/88/11/5478.
Travis, J. 2003. A new shot at fighting obesity? Science News Online (Sept. 6). Available at http://www.sciencenews.org/articles/20030906/food.asp.
______. 2002. Fullness factor: Gut hormone tells brain the stomach is well fed. Science News 162(Aug. 10):83. Available to subscribers at http://www.sciencenews.org/articles/20020810/fob2.asp.
______. 2002. Dieting woes tied to hunger hormone. Science News 161(June 8):366. Available to subscribers at http://www.sciencenews.org/articles/20020608/note15.asp.
______. 2002. The hunger hormone? Science News 161(Feb. 16):107-108. Available at http://www.sciencenews.org/articles/20020216/bob10.asp.
Williams, D.L. . . . D.E. Cummings, et al. 2003. Vagotomy dissociates short- and long-term controls of circulating ghrelin. Endocrinology 144(December):5184-5187. Available at http://endo.endojournals.
org/cgi/content/full/144/12/5184.
Sources:
Stephen R. Bloom
Department of Metabolic Medicine
Imperial College of Medicine
Hammersmith Hospital Campus
Du Cane Road
London W12 0NN
United Kingdom
Ian M. Chapman
Department of Medicine
University of Adelaide
Royal Adelaide Hospital
Adelaide, South Australia 5000
Australia
David E. Cummings
Department of Medicine
University of Washington
Box 358280, Mail Stop 111
Seattle, WA 98195
Ezio Ghigo
Department of Internal Medicine
University of Turin
Molinette Hospital
10126 Turin
Italy
Peter J. Havel
Department of Nutrition
University of California, Davis
One Shields Avenue
Davis, CA 95616
Arline Salbe
National Institutes of Health
4212 North 16th Street, Room 541
Phoenix, AZ 85016
Eve Van Cauter
University of Chicago
Department of Medicine
5841 South Maryland Avenue
Chicago, IL 60637
A.J. van der Lely
Section of Endocrinology
Department of Internal Medicine
Erasmus MCv40 Dr Molewaterplein
3015 GD Rotterdam
Netherlands
From Science News, Vol. 167, No. 14, April 2, 2005, p. 216.
Fattening revelations—and new mysteries—about the hunger hormone
Janet Raloff
Too busy to cook, you drop by the neighborhood café 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.
Dean MacAdam
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: http://www.sciencenews.org/articles/20020216/bob10.asp). 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 gut hormone that also appears to curb ghrelin manufacture.
D. MacAdam
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 (see Surprise!
Obesity (and Inactivity) Can Spur Cancers) (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."
D. MacAdam
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: Available to
subscribers at http://www.sciencenews.org/articles/20020706/note16.asp). Meanwhile, unhealthily lean people, such as those with anorexia nervosa, can have sky-
high background ghrelin concentrations.
D. MacAdam
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
(see A New Shot at Fighting Obesity).
"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?
D. MacAdam
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 caloric 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 gut 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.
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References:
Batterham, R.L. . . . and S.R. Bloom. 2003. Inhibition of food intake in obese subjects by peptide YY3–36. New England Journal of Medicine 349(Sept. 4):941-948. Available at http://content.nejm.org/cgi/content/full/349/10/941.
Broglio, F. . . . A.J. Van der Lely, et al. 2004. Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. Journal of Clinical Endocrinology & Metabolism 89(June):
3062-3065. Abstract available at http://intl-jcem.endojournals.org/cgi/content/abstract/89/6/3062.
Cohen, M.A. . . . and S.R. Bloom. 2003. Oxyntomodulin suppresses appetite and reduces food intake in humans. Journal of Clinical Endocrinology & Metabolism 88(October):4696-4701. Available at http://intl-jcem.
endojournals.org/cgi/content/full/88/10/4696.
Cummings, D.E., K.E. Foster-Schubert, and J. Overduin. 2005. Ghrelin and energy balance: Focus on current controversies. Current Drug Targets 6(March):153-169. Abstract available at http://www.ingentaconnect.
com/content/ben/cdt/
2005/00000006/00000002/art00003.
Cummings, D.E., et al. 2004. Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. American Journal of Physiology-Endocrinology and Metabolism 287(August):
E297-E304. Abstract available at http://ajpendo.physiology.org/cgi/content/abstract/287/2/E297.
Cummings, D.E., et al. 2001. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50(August):1714-1719. Available at http://diabetes.diabetesjournals.org/cgi/content/full/50/8/1714.
Gauna, C. . . . and A.J. van der Lely. 2005. Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes. Journal of Clinical Endocrinology & Metabolism 90(February):1055-1060. Abstract
available at http://intl-jcem.endojournals.org/cgi/content/abstract/90/2/1055.
Gauna, C. . . . and A.J. van der Lely. 2004. Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unacylated ghrelin strongly improves insulin sensitivity. Journal of Clinical
Endocrinology & Metabolism 89(October):5035-5042. Abstract available at http://intl-jcem.endojournals.org/cgi/content/abstract/89/10/5035.
Gelling, R.W. . . . D.E. Cummings, et al. 2004. Effect of uncontrolled diabetes on plasma ghrelin concentrations and ghrelin-induced feeding. Endocrinology 145(October):4575-4582. Abstract available at http://endo.
endojournals.org/cgi/content/abstract/145/10/4575.
le Roux, C.W. . . . and S.R. Bloom. 2005. Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. Journal of Clinical Endocrinology & Metabolism 90(February):
1068-1071. Abstract available at http://intl-jcem.endojournals.org/cgi/content/abstract/90/2/1068.
Overduin, J. . . . and D.E. Cummings. 2005. Role of the duodenum and macronutrient type in ghrelin regulation. Endocrinology 146(February):845-850. Abstract available at http://endo.endojournals.
org/cgi/content/abstract/146/2/845.
Salbe, A.D., et al. 2004. Negative relationship between fasting plasma ghrelin concentrations and ad libitum food intake. Journal of Clinical Endocrinology & Metabolism 89(June):2951-2956. Abstract available at http://intl-
jcem.endojournals.org/cgi/content/abstract/89/6/2951.
Spiegel, K. . . . and E. Van Cauter. 2004. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Annals of
Internal Medicine 141(Dec. 7):846-850. Abstract available at http://www.annals.org/cgi/content/abstract/141/11/846.
Spiegel, K. . . . and E. Van Cauter. 2004. Leptin levels are dependent on sleep duration: Relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. Journal of Clinical Endocrinology &
Metabolism 89(November):5762-5771. Abstract available at http://intl-jcem.endojournals.org/cgi/content/abstract/89/11/5762.
Sturm, K. . . . and I.M. Chapman. 2003. Appetite, food intake, and plasma concentrations of cholecystokinin, ghrelin, and other gastrointestinal hormones in undernourished older women and well-nourished young and
older women. Journal of Clinical Endocrinology & Metabolism 88(August):3747-3755. Available at http://intl-jcem.endojournals.org/cgi/content/full/88/8/3747.
Teff, K.L. . . . and P.J. Havel. 2004. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. Journal of Clinical Endocrinology &
Metabolism 89(June):2963-2972. Abstract available at http://intl-jcem.endojournals.org/cgi/content/abstract/89/6/2963.
Van der Lely, A.J., et al. 2004. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocrine Reviews 25(June):426-457. Abstract available at http://edrv.endojournals.
org/cgi/content/abstract/25/3/426.
Further Readings:
Batterham, R.L. . . . and S.R. Bloom. 2003. Pancreatic polypeptide reduces appetite and food intake in humans. Journal of Clinical Endocrinology & Metabolism 88(August):3989-3992. Available at http://jcem.endojournals.
org/cgi/reprint/88/8/3989.
Blom, W.A.M. . . . and H.F.J. Hendriks. 2005. Ghrelin response to carbohydrate-enriched breakfast is related to insulin. American Journal of Clinical Nutrition 81(February):367-375. Abstract available at http://www.ajcn.
org/cgi/content/abstract/81/2/367.
Broglio, F. . . . A.J. van der Lely, et al. 2003. Effects of ghrelin on the insulin and glycemic responses to glucose, arginine, or free fatty acids load in humans. Journal of Clinical Endocrinology & Metabolism 88(September):
4268-4272. Available at http://intl-jcem.endojournals.org/cgi/content/full/88/9/4268.
Broglio, F. . . . A.J. van der Lely, et al. 2003. The endocrine response to ghrelin as a function of gender in humans in young and elderly subjects. Journal of Clinical Endocrinology & Metabolism 88(April):1537-1542. Available
at http://intl-jcem.endojournals.org/cgi/content/full/88/4/1537.
Callahan, H.S., D.E. Cummings, et al. 2004. Postprandial suppression of plasma ghrelin level is proportional to ingested caloric load but does not predict intermeal interval in humans. Journal of Clinical Endocrinology &
Metabolism 89(March):1319-1324. Available at http://intl-jcem.endojournals.org/cgi/content/full/89/3/1319.
Christensen, D. 2002. Hunger hormone gone awry? Science News 162(July 6):14. Available to subscribers at http://www.sciencenews.org/articles/20020706/note16.asp.
de Graaf, C., et al. 2004. Biomarkers of satiation and satiety. American Journal of Clinical Nutrition 79(June):946-961. Available at http://www.ajcn.org/cgi/content/full/79/6/946.
Neary, N.M. . . . and S.R. Bloom. 2004. Ghrelin increases energy intake in cancer patients with impaired appetite: Acute, randomized, placebo-controlled trial. Journal of Clinical Endocrinology & Metabolism 89(June):2832-
2836. Abstract available at http://intl-jcem.endojournals.org/cgi/content/abstract/89/6/2832.
Raloff, J. 2002. Surprise! Obesity (and inactivity) can spur cancers. Science News Online (Aug. 3). Available at http://www.sciencenews.org/articles/20020803/food.asp.
Seppa, N. 2001. Weak appetite in elderly ties to hormone. Science News 160(Dec. 22):390. Available to subscribers at http://www.sciencenews.org/articles/20011222/fob6.asp.
Stock, S. . . . S.R. Bloom, et al. 2005. Ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide, and hunger responses to a mixed meal in anorexic, obese and control female adolescents. Journal of Clinical
Endocrinology & Metabolism 90(April):2161-2168. Abstract available at http://jcem.endojournals.org/cgi/content/abstract/90/4/2161.
Taheri, S., et al. 2004. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Medicine 1(December):e62. Available at http://dx.doi.org/10.1371/journal.pmed.0010062.
Tassone, F. . . . A.J. van der Lely, et al. 2003. Neuroendocrine and metabolic effects of acute ghrelin administration in human obesity. Journal of Clinical Endocrinology & Metabolism 88(November):5478-5483. Available at
http://intl-jcem.endojournals.org/cgi/content/full/88/11/5478.
Travis, J. 2003. A new shot at fighting obesity? Science News Online (Sept. 6). Available at http://www.sciencenews.org/articles/20030906/food.asp.
______. 2002. Fullness factor: Gut hormone tells brain the stomach is well fed. Science News 162(Aug. 10):83. Available to subscribers at http://www.sciencenews.org/articles/20020810/fob2.asp.
______. 2002. Dieting woes tied to hunger hormone. Science News 161(June 8):366. Available to subscribers at http://www.sciencenews.org/articles/20020608/note15.asp.
______. 2002. The hunger hormone? Science News 161(Feb. 16):107-108. Available at http://www.sciencenews.org/articles/20020216/bob10.asp.
Williams, D.L. . . . D.E. Cummings, et al. 2003. Vagotomy dissociates short- and long-term controls of circulating ghrelin. Endocrinology 144(December):5184-5187. Available at http://endo.endojournals.
org/cgi/content/full/144/12/5184.
Sources:
Stephen R. Bloom
Department of Metabolic Medicine
Imperial College of Medicine
Hammersmith Hospital Campus
Du Cane Road
London W12 0NN
United Kingdom
Ian M. Chapman
Department of Medicine
University of Adelaide
Royal Adelaide Hospital
Adelaide, South Australia 5000
Australia
David E. Cummings
Department of Medicine
University of Washington
Box 358280, Mail Stop 111
Seattle, WA 98195
Ezio Ghigo
Department of Internal Medicine
University of Turin
Molinette Hospital
10126 Turin
Italy
Peter J. Havel
Department of Nutrition
University of California, Davis
One Shields Avenue
Davis, CA 95616
Arline Salbe
National Institutes of Health
4212 North 16th Street, Room 541
Phoenix, AZ 85016
Eve Van Cauter
University of Chicago
Department of Medicine
5841 South Maryland Avenue
Chicago, IL 60637
A.J. van der Lely
Section of Endocrinology
Department of Internal Medicine
Erasmus MCv40 Dr Molewaterplein
3015 GD Rotterdam
Netherlands
From Science News, Vol. 167, No. 14, April 2, 2005, p. 216.
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