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University of Washington School of Medicine (H.S.C., D.E.C., M.S.P., P.A.B., C.C.M., D.S.W.) Seattle, Washington 98195; Veterans Affairs Puget Sound Health Care System (D.E.C.), Seattle, Washington 98108; and Harborview Medical Center (P.A.B., D.S.W.), Seattle, Washington 98104
Address all correspondence and requests for reprints to: David S. Weigle, M.D., Endocrinology, Box 359757, Harborview Medical Center, 325 Ninth Avenue, Seattle, Washington 98104. E-mail: weigle{at}u.washington.edu.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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If circulating ghrelin serves a critical physiological function in meal initiation in humans, it should fulfill several criteria. First, the progressive rise in plasma ghrelin level after a nadir should predict a spontaneous meal request, once a critical plasma level or rate of increase in this level occurs. This assertion has not been adequately tested by published studies in which subjects were fed on predetermined schedules and environmental cues that could elicit hunger were not carefully controlled (13, 14, 15, 16, 17). Second, experimental manipulations that alter the time course of ghrelin recovery after a nadir plasma value should produce corresponding alterations in the time to a spontaneous meal request, and the meal request should again be predicted by critical features of the plasma ghrelin profile. Finally, if meals of higher energy content produce greater satiety and delay to the request for a subsequent meal than meals of lower energy content (18, 19), then they should produce greater postprandial suppression of plasma ghrelin levels. As a corollary to this criterion, meals of no energy content should not suppress ghrelin. Consistent with this prediction, intragastric infusion of a glucose solution in rats and humans significantly suppresses plasma ghrelin levels, whereas intragastric infusion of the same volume of water does not suppress ghrelin (4, 20, 21). A recent study in humans, however, demonstrated that a meal of nonnutritive fiber suppressed postprandial plasma ghrelin levels to the same degree as did a 585-kcal test meal (22). Thus, the dependency of postprandial plasma ghrelin suppression on meal energy content and the effect of ghrelin recovery on the intermeal interval in freely eating humans remain to be elucidated.
The goal of this study was to determine whether ghrelin meets the criteria listed above for being a critical meal initiator in humans. We analyzed plasma ghrelin profiles in 10 subjects after the consumption of three standardized liquid meals (preloads) with widely varying caloric contents. The depth and duration of ghrelin suppression were assessed in relation to caloric content of the preloads, and we assessed whether the recovery of plasma ghrelin levels predicted the time of a subsequent spontaneous meal request in an environment devoid of cues related to time or food. Finally, we determined whether the plasma ghrelin level immediately before the spontaneous meal request predicted the number of calories consumed during that meal.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Ten healthy subjects (six women and four men) were recruited by means of posted advertisements. Subjects were at least 18 yr old and were weight stable to within 1 kg for at least 3 months before enrollment. Exclusion criteria included diabetes or other chronic disease, pregnancy, tobacco use, alcohol consumption of more than two drinks per day, unusual meal patterns (including no breakfast, breakfast before 0600 h, or breakfast after 1000 h), and a history of eating disorder (including restrained eating as measured by a three-factor eating questionnaire) (23). The median age of subjects was 22.5 yr (range, 18–46 yr), and the median body mass index was 22.6 kg/m2 (range, 19.3–25.3 kg/m2). Eligible subjects provided voluntary informed written consent before enrollment. All procedures and preload preparation took place at the General Clinical Research Center (GCRC), and the protocol was approved by the Human Subjects Review Committee of the University of Washington.
Study protocol
Volunteers were studied in the GCRC on three testing sessions lasting 10 h each and separated by intervals of at least 1 wk. Subjects served as their own controls for the consumption of preloads of three different caloric contents assigned in random order. Subjects were blinded to caloric content of the preload. The volume and macronutrient distribution of all three preloads were equivalent, and taste and viscosity differences of the preloads were masked as described below. Subjects were all studied in the same quiet private room with occlusive window drapes, a closed door, no external time cues (clocks, watches, computers, television, or radio), and no food cues (sight, smell, sound, or discussion of food).
Subjects arrived at the GCRC after an overnight fast, an intravenous catheter was placed in a forearm vein, and blood was drawn at 20-min intervals beginning at 0800 h. The preload was consumed between 0900 and 0915 h, and blood sampling continued until subjects requested a meal. Subjects were allowed to read, work, listen to recorded music, and engage in other light activities in the study room. The time of the spontaneous meal request was noted, after which the intravenous catheter was capped, and the subject was escorted to a hospital cafeteria where he or she freely selected a meal that was consumed after returning to the study room. The number of calories consumed during this meal was calculated using Nutrition Data System for Research software, Version 4.04 (Nutrition Coordinating Center, University of Minnesota, Minneapolis, MN; Food and Nutrient Database 32). Blood sampling resumed after the meal and was continued for another 80 min. Subjects remained in the study room until 1800 h on each of the 3 study days to remove any incentive to request a meal early so they could leave. At 1800 h, the intravenous catheter was removed, and the subject was discharged.
Preload preparation
The basal energy expenditure of each subject was calculated using the Harris-Benedict equation and multiplied by 1.6 to estimate total daily energy expenditure (24). The weight of each preload was held constant for each subject, and the energy density of the preload was adjusted to 0.5, 1.0, or 2.0 kcal/g, which corresponded to 7.5%, 16%, or 33% of estimated total daily energy expenditure. The macronutrient distribution of each preload was 35% carbohydrate, 45% fat, and 20% protein, formulated as shown in Table 1
. Differences in taste among the preloads were masked with sugar-free, fruit-flavored syrups and nonnutritive sweeteners, and texture differences were masked using unflavored gelatin granules, corn syrup, and fat-free Half & Half (Land O’Lakes, St. Paul, MN). Preloads were consumed through a straw from opaque, covered cups.
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Plasma immunoreactive ghrelin was measured using a commercially available RIA (Phoenix Pharmaceuticals, Belmont, CA) with a lower and upper detection limit of 80 and 2,500 pg/ml, respectively. The intraassay coefficient of variation was 8.7%, and the interassay coefficient of variation was 14.6%. Plasma insulin was measured using a double-antibody RIA (25). The lower and upper limits of detection were 2.2 and 300 µU/ml (13.2 and 1800 pmol/liter), respectively, and the intraassay coefficient of variation was less than 10%. All insulin samples from a single individual were run in duplicate in a single assay. Ghrelin samples were run in duplicate in a single assay for each subject if possible or in different assays that were normalized to one another using internal standards as described previously (13).
Statistical analysis
All ghrelin, insulin, and glucose time series data for each subject were normalized to the respective 0900 h baseline value, which was defined as time = 0 min, before computing mean values for graphic presentation. Within-subject comparisons among variables measured after the 7.5%, 16%, and 33% preloads were made using repeated measures ANOVA. Values for integrated area under the curve (AUC) of plasma insulin concentrations vs. time were calculated using the trapezoidal rule with identical time windows for each of the three preloads. The relationship between premeal plasma ghrelin level and calories ingested during the spontaneously requested meal was assessed by univariate regression analysis using a linear model. Statistical tests were considered significant at a level of P < 0.05. Statistical analyses were carried out using StatView 5.0.1 (SAS Institute, Inc., Cary, NC) and STATA 7.0 software (Stata Corporation, College Station, TX).
Plasma ghrelin levels and the time at which a meal was spontaneously requested covaried with the time interval after preload ingestion. Therefore, a Cox regression model was used to determine whether ghrelin level was associated with the time of a meal request. In this analysis, the last ghrelin level measured before a subject’s meal request was compared with the ghrelin levels taken at the same time from individuals who had not yet requested a meal (26). If plasma ghrelin level was an important determinant of a meal request, then the level of the subject requesting a meal should have been higher than the levels of subjects not requesting meals at that time. The Cox analysis accumulated these comparisons over time and also included a variable for energy content of the preload, because ghrelin levels and the time of a meal request also covaried with preload size. In this way, the data for all three preloads could be included in the same analysis, thereby maximizing the chance of finding a significant association between plasma ghrelin level and spontaneous meal request. The Cox analysis was performed separately for the following three time-dependent variables: plasma ghrelin level (% of baseline); slope of the ghrelin level over the three previous time points; and ghrelin levels integrated up to the time of meal request. To accommodate for the fact that each subject contributed an observation for each preload, a robust variance-covariance was used that acknowledged the statistical dependence between observations from the same subject (27).
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Results |
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, the AUC of plasma insulin after preload ingestion was directly proportional to the caloric content of the preload, with a highly significant difference between responses to the 33% and the 7.5% preloads. The AUC of plasma glucose levels after preload ingestion was equivalent among the three preloads, as expected for subjects with normal glucose tolerance (data not shown). The time between preload ingestion and spontaneous request for a subsequent meal was directly proportional to caloric content of the preload, and the number of calories consumed during the subsequent meal was inversely proportional to the caloric content of the preload (Table 2). Again, both of these parameters differed significantly between the 33% and the 7.5% preloads.
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, the mean normalized plasma ghrelin level after the 33% preload was significantly lower than that after the 7.5% preload at 60 min (P < 0.001), 120 min (P = 0.002), 180 min (P = 0.01), and 240 min (P = 0.03). The nadir plasma ghrelin levels and the last plasma ghrelin levels before spontaneous meal request after the three preload ingestions differed significantly from one another and are expressed as percent of the baseline (0900 h) ghrelin level in Table 2
. Averaging the time series of individual subjects causes the nadir values shown in Fig. 1 to appear higher and the premeal values to appear lower than the calculated mean values listed in Table 2. The recovery time for ghrelin was defined as the point after preload ingestion at which the plasma level returned to 90% of its baseline value. For statistical purposes, subjects that never reached this point were defined as having recovered at 300 min. Recovery occurred an average of 96 min later when the subjects consumed the 33% vs. the 7.5% preload (P = 0.005), and not all subjects’ ghrelin levels recovered (Table 2).
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, however, suggested that the plasma ghrelin profile was not a critical determinant of the meal request. There appeared to be no consistent threshold plasma ghrelin level or rate of change of the ghrelin level that immediately preceded a meal request. To make this assessment more quantitative, we performed a Cox regression analysis that controlled for both time after preload ingestion and preload caloric content as covariates of plasma ghrelin level in the timing of a meal request. In this analysis, the one-sided P value was >0.5 for association between the last ghrelin value before the meal request and time of the meal request. The relative risk of requesting a meal actually decreased with increasing ghrelin level (0.81 per 10% increase in ghrelin). A similar analysis revealed no relationship between time of meal request and slope of the ghrelin level over the three previous time points or for ghrelin levels integrated up to the time of the meal request. Finally, we used univariate linear regression analysis to determine whether the plasma ghrelin level immediately before the spontaneous meal request predicted the number of calories consumed during that meal. A relationship between these two variables might have been expected if ghrelin helps to determine the size of a meal. No significant relationship was found between ghrelin level and calories consumed for any of the preload groups considered separately (n = 10) or for the pooled data set (n = 30).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In addition to the absolute ghrelin level, we found that neither the slope nor the integrated area of the plasma ghrelin profile appeared to trigger meal initiation. Individual ghrelin profiles that were averaged to produce Fig. 1 were relatively flat or even declining for a variable period of time before the meal request. Furthermore, requests for a meal after the preload of highest caloric content generally occurred well before the plasma ghrelin level returned to the baseline value measured at 0900 h. The fact that our study was performed in an environment devoid of eating cues makes it unlikely that an association between the ghrelin profile and meal request was masked by external stimuli. It remains possible that some degree of recovery of ghrelin from its postprandial nadir value is required before other physiological stimuli can initiate a meal. In this sense, the rapid fall in ghrelin after a meal may act more as a signal not to eat than the recovery of ghrelin acts as a signal to eat.
Sugino et al. (16) demonstrated entrainment of the 24-h plasma ghrelin profile to feeding schedule in sheep. After Suffolk rams were trained to consume all food in one, two, or four meals per day, surges of ghrelin preceded each meal. In contrast, plasma ghrelin levels remained relatively low and constant in rams fed ad libitum. The authors interpreted their data as evidence for a cephalic ghrelin response that could be explained as a conditioned physiological reflex. Thus, although ghrelin administration may trigger a meal (1), neuroendocrine or psychological factors related to hunger may also prove to be a stimulus for ghrelin secretion.
Suppression of the plasma ghrelin level in proportion to caloric intake may serve other physiological functions. For example, ghrelin has been shown to stimulate gastric acid secretion and motility (8, 28), both of which increase in anticipation of meals at the time when ghrelin levels are highest. If gastric motility depends to some degree on ghrelin, then the decrease in ghrelin levels after initiation of a meal may modulate the rate of gastric emptying. Larger meals, which suppress ghrelin to a greater degree, may delay gastric emptying more than smaller meals, thereby preventing over-distension of the proximal small intestine.
A growing body of evidence suggests that ghrelin may participate in long-term energy balance, acting as a feedback signal modulating energy intake. States of sustained negative energy balance, including anorexia nervosa (22, 29), cancer anorexia (30, 31), cardiac cachexia (32), liver failure (33), and chronic caloric restriction (34), result in elevated plasma ghrelin levels. A trend toward suppression of ghrelin levels has been described with weight gain due to chronic overfeeding in humans (35), and others have demonstrated significant reduction in ghrelin levels accompanying weight gain from forced overfeeding in rats (Williams, D. L., D. E. Cummings, J. M. Kaplan, and H. J. Grill, unpublished data). Measures of body adiposity correlate negatively with baseline ghrelin levels, which is consistent with an inadequate compensatory role for ghrelin in common obesity (20, 35, 36, 37). The highest reported plasma ghrelin levels are in subjects with Prader-Willi syndrome, a condition characterized by extreme hyperphagia and obesity (37, 38, 39). Finally, manipulations capable of causing weight loss without compensatory hyperphagia, including gastric bypass surgery (34, 40, 41, 42) and low-fat diets (43), appear either to lower or prevent an increase in plasma ghrelin levels. Although ghrelin may not be required to regulate energy balance on a meal-to-meal basis, it may modulate appetite and central responses to other body composition signals in proportion to average meal size.
In summary, we found that postprandial suppression of plasma ghrelin levels was proportional to ingested caloric load but did not predict the intermeal interval in human subjects studied in an environment devoid of cues for eating. These findings do not negate the possibility that ghrelin participates in appetite control but show that, in the complex process of human meal initiation, other factors can determine the timing of individual meals. The current work does not address the possibility of a role for ghrelin in long-term energy homeostasis. It should be possible to clarify definitively the effect of ghrelin on appetite and meal initiation when specific antagonists of ghrelin action become available for use in clinical investigation.
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Acknowledgments |
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Footnotes |
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Abbreviations: AUC, Area under the curve; GCRC, General Clinical Research Center.
Received July 22, 2003.
Accepted November 18, 2003.
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