Ghrelin, hitherto known chiefly as an agonist of the growth hormone-secretagogue receptor with unclear physiologic functions, has emerged in the last 2 years as an important factor in the control of appetite and food intake and as an exciting potential target for antiobesity drugs. A symposium and numerous informative abstract presentations at ENDO 2003 focused the spotlight on the functions and regulation of this small gastrointestinal hormone.Regulation of Ghrelin Secretion
Ghrelin is a 28-amino acid peptide with a fatty acid side chain produced and secreted mainly by the X/A-like endocrine cells in the gastric fundus. Ghrelin may also be produced in the hypothalamus. Its levels in the blood are tightly linked to mealtimes. Specifically, the levels rise immediately preceding each meal and decline sharply following the meal. This raises the possibility that ghrelin signals to the brain a desire to eat and, following ingestion of the meal, sends a signal to "switch off" and terminate the desire to keep eating. The former effect has been reported in both animals and humans by the group of Dr. Stephen Bloom at Imperial College and the Hammersmith Hospital, London, United Kingdom. Work in several laboratories, notably those of Dr. Mark L. Heiman at Eli Lilly Laboratories, Indianapolis, Indiana, and Dr. David Cummings at the University of Washington, Seattle, has drawn attention to the meal- and energy-related regulation of ghrelin. Dr. Heiman provided a comprehensive review of his group's findings on the regulation of ghrelin secretion in a symposium entitled "Novel Factors in the Regulation of Energy Homeostasis."
The Lilly investigators used indirect calorimetry to measure the respiratory quotient (RQ) and total energy expenditure of rodents undergoing peripheral administration of exogenous ghrelin with or without a variety of dietary and caloric manipulations. Ghrelin increased the RQ, suggesting that the hormone preferentially increases oxidation of carbohydrates over that of other macronutrient substrates. A reverse or feedback regulation also appeared to occur, because oral ingestion of dextrose rapidly decreased endogenous plasma ghrelin levels.
To explore this concept further, the investigators measured substrate utilization in response to an oral ghrelin agonist. While feeding, the animals increased carbohydrate utilization, while sparing fat utilization for energy. However, while fasting, fat oxidation increased despite the ghrelin agonist. The net thrust of these complex results seems to be that ghrelin stimulates feeding behavior and during the consumption of a mixed meal perhaps favors carbohydrate oxidation. However, while fasting, ghrelin does not override the tendency to favor fat as the chief oxidative substrate.
Several reports have suggested an inverse correlation between insulin sensitivity and ghrelin levels in both humans and animals, raising the question of whether circulating glucose, circulating insulin, or some other factor modulated by insulin sensitivity is responsible for regulating ghrelin secretion. The investigators measured ghrelin levels in Zucker diabetic fatty rats before and after they became diabetic and found no differences in preprandial or postprandial ghrelin levels in the 2 conditions. They also found no correspondence between plasma ghrelin levels and those of insulin, glucose, or somatostatin in either state but a good correlation between glucagon and ghrelin levels.
Perhaps the most intriguing observation of this useful data set is the demonstration of what Dr. Heiman described as the possible role of ghrelin during the "cephalic phase" of regulation of nutrient metabolism. Rats normally shift to fat oxidation within minutes of being deprived of a source of food. Dr. Heiman's group therefore measured RQ in rats while fasting and after receiving a meal, visualizing a meal but not being able to eat it, or maintaining the fast without visualizing the meal. The RQ measurements indicated that the "true fed" animals made a sustained switch to carbohydrate oxidation, whereas the "true fasting" animals continued to maintain fat oxidation. Remarkably, the "trick fed" animals initially switched to carbohydrate oxidation (for the first 4 hours of visualizing but not consuming their meal) and then lapsed back to fat oxidation. This means that some trigger (perhaps visuoneural or neurohormonal) was switching fuel selection for oxidation -- a trigger associated with a rise in ghrelin levels. The "trick feeding" also increased insulin levels, raising the question of ghrelin's role either as an incretin or in regulating other incretins. Finally, food ingestion caused a rise in plasma levels of pancreatic polypeptide (PP), and PP is known to inhibit ghrelin secretion. So perhaps the postprandial PP rise is an "off" switch for ghrelin after a meal.Ghrelin and Sleep Deprivation
These fascinating experiments provide tantalizing but incomplete information about the complex regulation of this meal-related and meal-regulating orexigen. Other presentations at Endo 2003 provided additional insights into ghrelin's functions and regulation.
In an oral abstract session entitled "Obesity: Control of Appetite," Plamen Penev, MD, PhD, from the University of Chicago, Chicago, Illinois, presented data indicating an important role for ghrelin in the connection between sleep-wake cycles and feeding-fasting cycles.
Chronic sleep deprivation is generally associated with weight gain in humans and rodents and is also associated with increased activation of the sympathetic nervous system, which, in turn, is linked to decreased serum leptin levels. To probe the mechanism of sleep in maintaining energy balance, the investigators measured the relationship of sleep, hunger, sympathovagal activity, and leptin in human volunteers in a sleep laboratory. The volunteers were subjected to restricted nighttime sleep, extended nighttime sleep, or daytime bed rest, with continuous glucose infusions, sampling of leptin and ghrelin, visual analogue scales for hunger and appetite, and continuous monitoring of heart rate and ECG RR intervals (as a measure of sympathovagal balance).
The key result was that sleep deprivation resulted in an approximately 20% decline in the levels of leptin, with a corresponding increase in the levels of ghrelin and the sensations of appetite and hunger. Hunger correlated well with the ratio of serum ghrelin to serum leptin. Sleep deprivation was also accompanied by increased sympathetic activity, suggesting that this might mediate the effect of sleep loss on energy balance. It also suggests a direct link between central sleep-wake signals, sympathetic nervous activity, and ghrelin levels, since there is evidence from animals that increased sympathetic drive to the foregut of animals leads to increased ghrelin secretion.
This interesting study demonstrates that ghrelin is regulated by the sleep-wake cycle, possibly through central sympathetic control. It should also provide some solace to those insomniacs who are plagued by guilt for raiding the refrigerator at night; they may be fulfilling a biological drive rather than succumbing to the forces of gluttony.Ghrelin and Surgical Weight Loss Methods
Ghrelin levels rise before each meal and fall promptly after each meal. The amplitude of this unvarying pattern is modified by energy balance. For example, following weight loss due to a low-calorie diet, the pattern is preserved but the levels of ghrelin increase, presumably as an adaptive response to constrain weight loss. This might lead to increased appetite and tend to mitigate the effectiveness of the diet. Since ghrelin is released by cells in the gastric fundus, the relation of ghrelin levels to the weight loss resulting from bariatric surgery has generated much interest. Furthermore, there appear to be 2 mechanisms underlying the weight loss in such circumstances: (1) decrease in caloric intake and (2) decrease in appetite.
The group of David E. Cummings, MD, at the University of Washington, Seattle, asked if something different about the ghrelin response might account for the effectiveness of gastric surgical methods to induce weight loss in obese persons. Typically, gastric bypass procedures, which both restrict the capacity of the stomach and induce malabsorption, cause not only early satiety but also a marked loss of hunger. However, the relationship of ghrelin to these changes is not straightforward. After gastric bypass, where ghrelin levels might be expected to increase (secondary to the absence of the suppressive signal of food in the stomach), they actually are very low. Could this apparent paradox be due to the complete absence of prandial variations experienced by the stomach?
Dr. Cummings presented data from an experiment to test this hypothesis. The Seattle investigators examined the effects of gastric banding, a procedure that also restricts stomach size but still requires food to pass through the stomach. The serum ghrelin levels of 15 obese subjects were inversely correlated with body mass index and fat mass. Eight months after gastric banding, they experienced marked decreases in caloric intake and weight; however, ghrelin levels were actually higher than before the surgery.
There is not an easy physiologic explanation for these differential responses of ghrelin to the different kinds of bariatric surgery, especially because the direction of ghrelin change is not what one would anticipate from a simple meal-related regulation of the hormone. Whole-body energy balance might have independent effects on ghrelin secretion, suggesting other neurohormonal mechanisms of regulation. There may also be other caveats in interpreting these new findings. For instance, not all studies of patients undergoing gastric bypass surgery have shown declines in ghrelin levels, so the degree of weight loss, or the extent of autonomic denervation that accompanies different gastric bypass techniques, might produce different effects.
Dr. Simon Aylwin, MD, of King's College Hospital, London, United Kingdom, presented the results of an experiment designed to probe further the mechanisms underlying the differences in weight loss induced by the 2 forms of gastric surgery. Reasoning that ghrelin (a meal-regulated orexigenic signal) and peptide YY (PYY, a meal-regulated anorexigenic signal) might have opposing effects on caloric intake and appetite with every meal, they measured the response of PYY to a meal in 12 lean persons, 12 obese persons, and 12 obese persons after bariatric surgery (6 who had undergone gastric bypass and 6 who had undergone gastric banding). The postprandial serum levels of PYY were higher in the lean subjects than in the obese subjects. The obese subjects who had undergone bariatric surgery had higher postprandial PYY levels than both the control groups, and those who had undergone gastric bypass (ie, gastric restriction plus malabsorption) had significantly higher PYY levels than those who had undergone gastric banding (ie, gastric restriction alone).
Several provocative conclusions are suggested from these results. Ghrelin and PYY might affect appetite reciprocally and might regulate -- and be regulated by -- each meal. The increased surge in postprandial PYY levels following gastric bypass may be responsible for the greater suppression in appetite than that following gastric banding. Hence, the meal-related regulation of appetite is modulated by at least 2 opposing gastric hormones. Is it reasonable to predict that there may be other factors as well?References
Heiman MH, Woodson AL, Craft LS, Dodge JA. Basic science symposium: novel factors in the regulation of energy homeostasis. Program and abstracts of the 85th annual meeting of the Endocrine Society; June 19-22, 2003; Philadelphia, Pennsylvania.
Penev P, Hudson L, Spiegel K, et al. OR 33-1: impact of sleep curtailment on sympathovagal balance, leptin levels, hunger and appetite. Program and abstracts of the 85th annual meeting of the Endocrine Society; June 19-22, 2003; Philadelphia, Pennsylvania.
Cummings DE, Coupaye M, Frayo RS, Guy-Grand B, Basdevant B, Clement K. OR33-3: weight loss caused by adjustable gastric banding increases plasma ghrelin levels in humans. Program and abstracts of the 85th annual meeting of the Endocrine Society; June 19-22, 2003; Philadelphia, Pennsylvania.
Le Roux C, Aylwin SJB, Coyle F, Ghatei M, Patel A, Bloom SR. OR33-2: meal-stimulated release of the putative satiety hormone PYY in severe obesity and following gastric bypass surgery. Program and abstracts of the 85th annual meeting of the Endocrine Society; June 19-22, 2003; Philadelphia, Pennsylvania.
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Cite this: Ashok Balasubramanyam. Ghrelin and PYY: Rising Stars in Appetite Regulation - Medscape - Aug 07, 2003.