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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 4 1727-1732
Copyright © 2004 by The Endocrine Society

Fasting and Postprandial Total Ghrelin Remain Unchanged after Short-Term Energy Restriction

Eric Doucet, Marjorie Pomerleau and Mary-Ellen Harper

School of Human Kinetics (E.D., M.P.) and Department of Biochemistry, Microbiology, and Immunology (M.-E.H.), University of Ottawa, Ottawa, Ontario, Canada K1N 6N5

Address all correspondence and requests for reprints to: Dr. Eric Doucet, School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5. E-mail: edoucet{at}uottawa.ca.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Adaptations that promote positive energy balance appear in response to dietary restriction. The aim of this study was to determine whether fasting and postprandial total ghrelin increase in response to short-term energy restriction. Fifteen adult male subjects were subjected to a 4-d energy restricted diet (–800 kcal/d). Body weight and composition, resting energy expenditure, respiratory quotient, fasting and postprandial appetite scores, and fasting and postprandial serum leptin and total ghrelin were determined before and after dietary intervention. Despite the fact that fat mass remained unchanged after the 4 d, fasting (–36%; P <= 0.01) and postprandial serum leptin (–27%; P = 0.01) were significantly reduced. A significant reduction in total ghrelin was observed after the meal (P <= 0.05); however, fasting and postprandial total ghrelin remained unchanged at the end of the intervention. Although leptin was a significant correlate of appetite before and after the intervention, no such associations were noted for total ghrelin. Finally, a significant relation between total ghrelin and respiratory quotient was noted at the onset of the diet (r = 0.63; P <= 0.01). Fasting and postprandial total ghrelin levels remain unchanged after short-term energy restriction despite a significant fall in leptin.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
A REANALYSIS OF the Minnesota semistarvation study by Keys et al. (1) revealed that humans overshoot their prestarvation body fat when free access to food is again made possible (2). This finding supports the idea that prolonged energy deprivation induces effects that in return favor a sustained positive energy balance. In fact, unfavorable changes in energy expenditure (3, 4), substrate partitioning (5), and appetite (6) appear in response to negative energy balance mitigating weight loss. These adaptations are possibly responsible for the weight relapse observed in a great proportion of individuals who undergo weight loss therapy (7, 8) and for the resistance to slimming in others. Clearly, the energy-restricted state is not a benign condition and counterregulatory responses seem to exist.

Circulating peptides and other factors related to energy balance fluctuate in response to prolonged negative energy balance. As such, the fact that fat loss triggers a decrease in leptin is now well recognized (9, 10, 11, 12). Also, this fall in leptinemia is independently associated with changes in energy expenditure (10), fat oxidation (13), and appetite (6, 14) that result from weight loss. It is also probable that such adaptations appear early in the energy-restricted state, in agreement with the concept that an important role of leptin is to trigger actions that favor the preservation of energy reserves during periods of lowered food availability (15, 16).

Ghrelin, a ligand for the GH secretagogue receptor, is an orexigenic peptide that is predominantly secreted by the oxycintic gland of the stomach (17). The fact that ghrelin is reduced in obesity (18, 19) and increased in anorexia nervosa (20) and in response to sustained energy restriction leading to weight loss (21, 22) suggests an important role for this peptide during long-standing energy imbalance. It has been shown that the preprandial rise in ghrelin might serve as a meal initiation signal (23). Accordingly, iv administration increases appetite and food intake (24), whereas the infusion of glucose into the stomach (25) and the ingestion of a meal (26) seem to decrease its levels, although this suppression is less apparent in obesity (27).

It is now clear that fasting lowers circulating leptin (28, 29, 30, 31) and that, conversely, ghrelin is increased under such conditions (26). However, to our knowledge no study has examined the short-term effects of an energy restriction regimen typical of that used for weight loss on ghrelin and leptin levels and their potential associations with appetite scores under such conditions.

We hypothesized that the early fall in leptin during energy deprivation would be accompanied by an increase in circulating total ghrelin, leading to increases in appetite in some subjects. The aim of this study was thus to determine whether changes in fasting and postprandial total ghrelin appear in response to a short-term, energy-restricted diet and whether associations with appetite could be observed under such conditions. A secondary aim of this study was to investigate the associations between leptin and ghrelin and resting energy metabolism under these conditions.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Fifteen apparently healthy male (determined by a medical history questionnaire) subjects participated in this study. The average age was 24.4 ± 4.4 yr. The subjects were recruited among the University of Ottawa student body to undergo a 4-d energy restriction (–800 kcal/d). Participants had been weight stable for at least 6 months before their enrolment in the study. The energy restriction was established from a resting energy expenditure (REE) measurement made 1 wk before the start of the intervention. All subjects were instructed to refrain from vigorous exercise for 48 h, to eat as they would normally, and to avoid alcohol and stimulants (e.g. caffeine and spicy foods) for 24 h before this measurement. Because subjects were sedentary at the onset of the program, an activity factor of 1.4 was used to estimate 24-h energy needs from REE values (kilocalories per minute x 1440 min x 1.4). From this value, 800 kcal were subtracted to obtain daily energy intake for the hypocaloric intervention. The macronutrient composition of the prescribed diet was as follows: 55% carbohydrates, 30% fat, and 15% protein. Participants then adhered to the dietary prescription for 4 d. Baseline measurements were taken on the morning of d 1, whereas postintervention measurements were performed on the morning of d 5. Both baseline and postintervention measurements were taken after 12-h overnight fasts. An overview of the protocol is shown in Fig. 1Go. Subjects gave their written consent to participate in this study that received approval of the research and ethics board of University of Ottawa.



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  		FIG. 1. Study protocol.

 
Anthropometric measurements

Body weight was taken with a standard beam scale, whereas body density was determined by hydrodensitometry (32). The Siri formula (33) was used to estimate the percentage of body fat from body density, whereas fat mass (FM) and fat-free mass (FFM) were calculated from the percentage of body fat and total body weight. Waist circumference was also assessed before and after intervention at the level of the umbilicus.

Standardized breakfast test meal

The response to a standardized breakfast test meal was examined before and after the 4-d energy restriction period. Subjects reported at the laboratory after a 12-h overnight fast. In all cases, the test meal was consumed between 0800 and 0815 h. The meal consisted of two slices of whole wheat bread (80 g), peanut butter (20 g), strawberry jam (20 g), cheddar cheese (27% milk fat; 20 g), and orange juice (250 ml). The total energy content was 2400 kJ (575 kcal), and its food quotient was 0.89. Subjects were instructed to eat everything within a 20-min period (all finished within 10 min). The caloric equivalent and the macronutrient composition of this meal were standardized to assess the effects of the energy restricted diet per se on postprandial appetite sensations and peptides.

Visual analog scale measurements

Desire to eat, hunger, fullness, and prospective food consumption (PFC) were rated on a 150-mm visual analog scale (VAS) that was adapted from Hill and Blundell (34). These measurements were conducted immediately before the test meal and at 0815, 0830, 0845, 0900, and 0915 h after the ingestion of the standardized breakfast test meal before and after the 4-d intervention. Questions were asked as follows. 1) How strong is your desire to eat (very weak to very strong)? 2) How hungry do you feel (not hungry at all to as hungry as I have ever felt)? 3) How full do you feel (not full at all to very full)? 4) How much food do you think you could eat (nothing at all to a large amount)?

Noteworthy is the fact that VAS measurements were always performed by the same investigator in the same environment, i.e. at the same table with the same lighting in the same room, which was kept free of odors and sounds as well as other factors that could have confounded measurements. Under such conditions, VAS as been to shown to be reliable and reproducible (35, 36).

Reported energy intake

To obtain an index of the compliance of subjects with the dietary prescription, reported energy intake was assessed by means of a 3-d dietary record during d 2, 3, and 4 of the dietary intervention. A nutritionist explained to subjects individually how to complete their records. Finally, on the collection day the record was reviewed by the nutritionist with the subject. Data from the records were then analyzed by computer using the Canadian Nutrient File (37) to calculate energy and macronutrient intakes.

REE

Before and after the 4-d intervention, REE was measured for 20 min after a 20-min resting period following an overnight fast (at 0720 h), while subjects were in the supine position. Pulmonary ventilation, oxygen consumption, and carbon dioxide production were assessed by open-circuit spirometry (250 l, chain-compensated gasometer, Warren Collins, Inc., Braintree, MA). A mouthpiece, a unidirectional valve (2700 series, Hans Rudolph, Kansas City, MO), and a 44-mm plastic tube were used to direct all expired gases to the collection tank. Expired gases were collected for 1 min every 5 min during the measurement. Oxygen and carbon dioxide concentrations in expired gases were determined using calibrated electrochemical gas analyzers (AMETEK model S-3A/1 and CD 3A, Applied Electrochemistry, Pittsburg, PA). This system was calibrated before each test, and the Weir formula (38) was used to determine the energy equivalent of oxygen volume.

Serum leptin and total ghrelin assays

Immediately after sampling, blood was allowed to cloth at 4 C for 1 h, after which it was centrifuged at 3000 rpm for 5 min at 4 C. Serum was obtained from these samples and immediately stored at –75 C until assayed. Leptin concentrations were measured from fasting and postprandial serum samples (60 min after the standardized breakfast at 0915 h). Serum leptin concentrations were assayed with a commercial double-antibody RIA (Human Leptin Specific RIA Kit, Linco Research, Inc., St. Louis, MO). Total serum ghrelin levels were also assayed with a commercial double-antibody RIA (Human Total Ghrelin Specific RIA Kit, Linco Research, Inc.) after an overnight fast as well as at 0815 h (immediately after), 0845 h (30 min), and 0915 h (60 min) into the postprandial state. This sampling procedure was adopted considering results that have shown a strong correlation between samples taken early in the morning in the fasting and postprandial states and 24-h ghrelin levels (23).

Statistical analysis

The SPSS software 11.5 package (SPSS, Inc., Chicago, IL) was used for all analyses. A one-way ANOVA for repeated measures (baseline and postintervention) was used to assess the effects of the 4-d energy restriction on anthropometric variables. Repeated measures ANOVA with two within-subject factors [effects of intervention (pre and post) and effects of the meal] were used for appetite scores as well as for leptin and total ghrelin. Prescribed and reported energy intakes were compared by paired t tests. Spearman’s Rho rank order correlations were used to determine the nature of relations between leptin and total ghrelin and appetite sensations before and after the intervention, whereas partial correlation analyses controlling for FM and FFM were performed between leptin and ghrelin, and REE and respiratory quotient (RQ) were determined before and after the intervention. All data are expressed as the mean ± SD, and effects were considered significant at P <= 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The characteristics of the subjects are presented in Table 1Go. Body weight (–1.3 kg; P <= 0.01), FFM (–1.5 kg; P <= 0.01), body mass index (–0.4; P <= 0.01), and waist circumference (–0.7 cm; P <= 0.05) were all significantly reduced at the end of the intervention. In contrast, FM was unchanged as a result of this intervention.


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  		TABLE 1. Subjects’ characteristics before and after the 4-d energy-restricted diet

 
Prescribed and reported energy intakes were not significantly different; values were 1820 ± 107 and 1903 ± 134 kcal/d, respectively. Reported (55% carbohydrate, 25% fat, and 20% protein) and prescribed (55% carbohydrate, 30% fat, and 15% protein) macronutrient compositions were also essentially the same despite the fact that fat intake was lower and protein intake higher than those prescribed. The fact that the prescribed energy intake was not significantly different from the energy intake reported by subjects during the intervention indicates the compliance of subjects to the dietary prescription.

Appetite scores measured with a VAS are presented in Fig. 2Go. As expected, a significant effect of the meal was observed (P <= 0.01), indicating decreases in the desire to eat, hunger, and PFC and an increase in fullness in response to the meal. In addition, a significant effect of the intervention (pre- vs. postenergy restriction) was only observed for hunger scores (P <= 0.05), with desire to eat and PFC displaying strong trends (P <= 0.1).



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  		FIG. 2. Fasting and postprandial desire to eat, hunger, fullness, and prospective food consumption (PFC) before ({blacksquare}) and after ({diamondsuit}) the 4-d energy restriction. There was a significant effect of the meal on all four variables (P <= 0.01) and a significant effect of the intervention on hunger (P <= 0.05). Trends were also noted for desire to eat and PFC (P <= 0.1).

 
Fasting and postprandial serum leptin values are presented in Fig. 3Go. As expected, a significant fall in both fasting and postprandial leptin was observed at the end of the intervention (P <= 0.01). In fact, fasting serum leptin was decreased by 36%, whereas postprandial values were 27% lower at the posttreatment sampling. In addition, a trend toward a reduction of leptin levels was seen 1 h after the meal (P = 0.07). The effects of the intervention on fasting and postprandial serum leptin also serve as an index of the compliance of participants with the dietary prescription.



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  		FIG. 3. Fasting and postprandial serum leptin (60 min after the meal) before ({blacksquare}) and after ({diamondsuit}) the 4-d energy restriction. The effect of the meal (P <= 0.1) and the effect of the intervention (P <= 0.01) were significant.

 
Fasting and postprandial total serum ghrelin values are presented in Fig. 4Go. Fasting and postprandial total serum ghrelin levels were essentially the same before and after the intervention (P = 0.7). As expected, a significant effect of the meal was noted for this peptide (P <= 0.05).



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  		FIG. 4. Fasting and postprandial total serum ghrelin before ({blacksquare}) and after ({diamondsuit}) the 4-d energy restriction. There was a significant effect of the meal (P <= 0.05).

 
Spearman’s Rho rank order correlations were performed to assess whether appetite scores were related to leptin and total ghrelin before and after the intervention (Table 2Go). Leptin was the only significant correlate of appetite before and after the intervention. Fasting PFC (r = –0.45; P <= 0.05) and fullness (r = 0.47; P <= 0.05) were both significantly associated with leptin at the onset of the dietary prescription, whereas postprandial fullness was the only significant correlate of leptin (r = 0.43; P <= 0.05) at the end of the intervention. No significant associations of total ghrelin with appetite scores were noted.


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  		TABLE 2. Correlation coefficients of fasting and postprandial appetite scores with serum leptin and total ghrelin before and after the 4-d energy-restricted diet

 
REE was not changed at the end of the energy-restricted diet (1.23 vs. 1.26 kcal/min, respectively; P = NS). As expected, RQ tended to decrease in response to the intervention (0.89 vs. 0.84; P = 0.08). Partial correlation analyses controlling for FM and FFM were performed to investigate the contribution of fasting total ghrelin and leptin to REE and RQ before and after the 4-d restriction. These analyses revealed that RQ was positively associated with total ghrelin before (r = 0.63; P = 0.01), but not after, the intervention (r = 0.27; P = 0.18; P = NS). No significant correlation between plasma leptin and RQ was observed. However, leptin tended to be correlated to REE before weight loss (r = 0.40; P = 0.08).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The main finding of this study was that despite successful adherence to an energy-restricted diet, as reflected by both the similitude between prescribed and reported energy intakes and the important reduction in leptin (~30%), both fasting and postprandial total serum ghrelin do not seem to be influenced by short-term energy restriction. Thus, ghrelin did not mitigate the effects of a hypocaloric diet on weight loss under the conditions of this study.

The fact that prolonged energy deprivation is associated with an increase in appetite is well known and has been recently documented (6). Of particular interest to this study is the fact that changes in appetite that occur in response to weight loss have been associated with leptin (14). In addition, recent evidence has shown that the administration of pegylated recombinant leptin to humans favorably affects the appetite profile during the course of weight loss compared with the effect of placebo (39). The association between leptin and appetite reported in this study suggests that a marked decrease in circulating leptin occurs very quickly after the beginning of an energy-restricted diet and could reduce the adherence to hypocaloric dietary therapy.

Contrary to the effects of leptin, the orexigenic peptide ghrelin recently isolated from gastric extracts (17) has been shown to increase appetite and energy intake when administered iv to human subjects (24) and to increase in response to weight loss (21, 22). Also, despite the fact that an overnight fast increases ghrelin levels significantly (26) and that increases in appetite have been demonstrated under similar conditions (28), to our knowledge no data exist on the short-term effects of energy restriction on fasting and postprandial ghrelin levels and the association of the peptide with appetite in human subjects. Recent observations have evidenced an increase in circulating ghrelin after 1 wk of caloric restriction (–25% of weight maintenance intake) in rodents. The results reported in this paper show that both fasting and postprandial total ghrelin levels were unchanged after short-term energy restriction, even if leptin was substantially decreased. These findings are inconsistent with the idea that leptin and ghrelin act synergistically in the preservation/restoration of energy reserves (40, 41). Although numerous studies have shown that ghrelin is increased in response to sustained negative energy balance leading to weight loss (21, 22), it is possible that such an effect needs considerable reductions in energy reserves before becoming apparent. As such, it would seem that ghrelin does not blunt the effects of a weight loss diet at the beginning of such an intervention. It should nonetheless be pointed out that circulating ghrelin signaling has been shown to occur through vagal afferents in animals (42), possibly affecting energy homeostasis without any noticeable changes in circulating ghrelin levels. Another important factor that deserves mention is the fact that it is often assumed that total ghrelin is equivalent in effect to its biologically active form. Because total ghrelin does include both octanoylated and des-octanoylated forms, this factor needs to be taken into account when drawing conclusions based on variations in total ghrelin.

It was recently shown that a lesser increase in circulating ghrelin is observed when the diet used to induce weight loss has a high carbohydrate content (40). This coincides with results demonstrating that gastric infusions of glucose considerably reduce ghrelin levels (25). Our diet also had a relatively high carbohydrate content (55%). Although Weigle et al. (40) employed a carbohydrate content of 65%, this similarity raises the possibility that the absence of change in total ghrelin in the present study could be explained by the high carbohydrate content of the energy-restricted diet. Further research will be needed to assess whether macronutrient manipulations aimed at increasing the satiating potential of weight loss diets (e.g. increasing protein content) (43) also favorably impact on ghrelin profiles.

Previous reports have shown that ghrelin is considerably reduced in response to food and nutrient intake (26, 44). At this point, it is important to point out that postprandial suppression of ghrelin might not be as apparent in obese subjects (27). Nonetheless, our results support earlier findings, as postprandial total ghrelin levels were somewhat lower than fasting values despite the fact that no effect of energy restriction was observed. Because our sampling procedure was relatively shorter than that used previously, it might be argued that we did not capture the full effect of the meal on total ghrelin levels. It should be noted, however, that the sampling time frame was adopted to obtain fasting and postprandial values soon after waking (30–60 min). These values have been reported to be highly correlated to the 24-h ghrelin profile (23).

The decrease in leptin that accompanies weight loss has been extensively documented (45). Of interest to this study is the fact this peptide drastically drops early in the course of weight loss programs out of proportion to changes in FM (11). In fact, 48- to 72-h fasts have been shown to affect leptin levels to a significant extent (28, 29, 30, 31, 46). These early effects are concordant with the idea that leptin variations are aimed at reestablishing energy balance by influencing both appetite and energy metabolism (15, 16, 28). The results of previous research lend support to this theory, as leptin has been shown to be independently associated with the changes in energy expenditure (10) and fat oxidation (13) that occur in response to weight loss. In this sense, recent results also show that when recombinant leptin is administered iv, it attenuates the drop in REE that normally occurs during energy-restricted diets (47). To our knowledge, the results presented herein are the first to show that leptin is reduced substantially shortly after the initiation of an energy-restricted diet that is typical of a diet used to induce weight loss. However, we were unable to evidence a relationship among REE, RQ, and leptin under these conditions. Further research will be needed to detail how early variations in leptin impact on the outcome of weight loss programs.

Few studies have examined the effects of ghrelin on energy expenditure and substrate partitioning. Infusion of ghrelin to rats has been shown to increase RQ and favor fat gain (48). To our knowledge, no report on the relation between ghrelin and energy expenditure or substrate partitioning is available in human subjects. As such, our results are the first to show that total ghrelin is significantly associated with whole body RQ in human subjects. Because a high RQ has been shown to predict body weight gain and regain (49, 50, 51), it is possible that the increase in ghrelin observed at the end of a weight loss program (21, 22) could contribute to the reduced fat oxidation under such conditions (5) and possibly to weight regain as well. More research will be needed to confirm this hypothesis.

In summary, despite a significant increase in appetite and a marked reduction in circulating leptin shortly after the beginning of the energy restriction typical of that used to induce weight loss, we were not able to evidence an increase in circulating total ghrelin, nor were we able to show any relation between appetite score and total ghrelin under such conditions. We thus conclude that total ghrelin probably does not function to increase appetite early in a hypocaloric dietary regimen.


   Acknowledgments
 
We express our appreciation to Lisa Bevilacqua, Sheila Costford, and Mahmoud Salkordeh for their expert technical assistance with the peptide assays.


   Footnotes
 
Abbreviations: FFM, Fat-free mass; FM, fat mass; PFC, prospective food consumption; REE, resting energy expenditure; RQ, respiratory quotient; VAS, visual analog scale.

Received August 21, 2003.

Accepted December 23, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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