410 Humans, Clinical
Effect of Moderate-intensity Exercise Session on Preprandial and Postprandial Responses of Circulating Ghrelin and Appetite
Authors
D. Malkova1, R. McLaughlin1, 3, E. Manthou1, A. M. Wallace2, M. A. Nimmo4
Affiliations
1
Human Nutrition Section, Division of Developmental Medicine, Medical School, University of Glasgow, United Kingdom Department of Clinical Biochemistry, Medical School, University of Glasgow, United Kingdom 3 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom 4 School of Sport and Exercise Sciences, Loughborough University, United Kingdom 2
Key words 䉴 ghrelin 䊉 䉴 cytokines 䊉 䉴 insulin 䊉 䉴 leptin 䊉 䉴 appetite 䊉
received 07.05.2007 accepted 15.10.2007 Bibliography DOI 10.1055/s-2008-1058100 Published online: March 14, 2008 Horm Metab Res 2008; 40: 410–415 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence Prof. M. A. Nimmo School of Sport and Exercise Sciences Loughborough University Ashby Road Loughborough Leicestershire LE11 3TU United Kingdom Tel.: + 44 (0)1509/22 63 11 Fax: + 44 (0)1509/22 63 01 m.a.nimmo@lboro.ac.uk
Abstract & Responses of plasma total ghrelin and appetite were investigated during preprandial and postprandial stages of recovery from a moderateintensity cycling session. Healthy recreationally active men underwent one exercise and one control trial. In the exercise trial, subjects exercised for approximately 60 minutes, while in the control trial they rested quietly for the same duration. After the intervention, subjects rested for 120 minutes and then consumed a test meal. Measurements were obtained immediately and 120 minutes after the intervention and then during 180 minutes of the postprandial period. The post-intervention concentration of total ghrelin was lower (p < 0.05) in the exercise than in the
Introduction & Ghrelin is a 28-amino-acid peptide primarily secreted by endocrine cells in the gastrointestinal tract [1–3] and is found in the circulation of healthy humans in both acylated and desacyl forms [4]. Initially, ghrelin was known as a potent stimulus for growth hormone secretion [2], but it was soon suggested that ghrelin is also a potent orexigenic substance [5, 6] that crosses the bloodbrain barrier and stimulates food intake by acting on several classical body-weight regulatory centres [7]. Accumulating evidence suggests that ghrelin secretion is upregulated under conditions of negative energy balance and downregulated in the setting of positive energy balance [8–12], which suggests an important role for this peptide during long-term energy imbalance. At the same time, studies reporting a preprandial rise in humans, whether being fed on a known schedule or initiating meals voluntarily without time- or food-related cues, together with a significant
Malkova D et al. Ghrelin and Appetite Following Exercise … Horm Metab Res 2008; 40: 410–415
control trial. The modulating effect of exercise was related to the reduction in the postprandial rather than preprandial concentration. Postintervention scores of appetite were not different between the two trials, but when preprandial and postprandial responses were considered separately, postprandial hunger and desire to eat was higher (p < 0.05) in the exercise trial. In summary, during recovery from moderate-intensity exercise, total ghrelin does not respond in a compensatory manner to disturbances in energy balance. Thus, an exercise-induced increase in appetite during the later stages of recovery coinciding with the postprandial state cannot be explained by changes in the plasma concentration of total ghrelin.
suppression after feeding suggest that ghrelin participates in the determination of food intake from meal to meal [13, 14]. Accordingly, it has been shown that intravenous administration of ghrelin enhances appetite and increases food intake in humans [6, 15]. Circulating concentrations of ghrelin have been reported to be unchanged after a single exercise session of running or cycling at moderate intensity [16–20] and after rigorous treadmill running [18, 21]. Long- or medium-term training studies also have shown no effect of exercise on total ghrelin independent of its impact on body weight [22, 23], with one of these studies reporting an increase in acylated ghrelin after aerobic training for five consecutive days [23]. In contrast there are reports of a significant decrease in total ghrelin concentration after concentric muscle actions [24], single circuit resistance exercise [25], and a standardised maximal exercise test [26]. In addition, a recent study reported that running exercise reduces plasma concentrations of acylated
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ghrelin and that this suppression lasts for as long as eight hours after exercise [27]. Given the present worldwide increase in the prevalence of obesity and the knowledge that physical inactivity is a significant contributing factor [28], an understanding of how ghrelin and exercise interplay to impact on appetite and thus energy balance is of great importance. Unfortunately, only a few of the exercise and ghrelin studies considered appetite measurements [19, 23, 27]. Findings of these studies suggest that during the early hours of post-exercise recovery, changes in fasting appetite may be predicted by changes in acylated ghrelin [23, 27] but not total ghrelin [19] and that during the later stages of post-exercise recovery that coincide with postprandial state, the appetite regulatory role of acylated ghrelin is diminished [27]. The main aim of this study was to investigate the impact of a single moderate-intensity exercise session with duration to expend 2.1 MJ on subjective measures of appetite and concentrations of plasma ghrelin in preprandial and postprandial states of a recovery period lasting for five hours. Furthermore, given the reported role of insulin, leptin, and interleukin-6 (IL-6) in the regulation of circulating ghrelin and appetite [29–32], we also investigated changes in these hormones.
Materials and Methods & Subjects Eleven healthy, recreationally active men with the following characteristics (mean ± SD): age 23.8 ± 5.8 years; body mass index 23.3 ± 2.9 kg/m2; body fat level 13.7 ± 3.4 %; V˙ O2 peak 41.8 ± 7.2 ml/kg/min, participated in the study, after giving their written informed consent to the study protocol, which was approved by the Ethics Committees of Strathclyde and Glasgow Universities. None of the subjects was a smoker, was on any special diet, or was taking self-medicated or prescribed medication.
Study design Prior to the first main trial, subjects attended the laboratory for lactate threshold (LT) and peak oxygen uptake (V˙ O2 peak) determination. They subsequently underwent two trials, one control and one exercise, in a balanced design separated by at least three days. In the exercise trial, the intervention involved cycling at 90 % of LT for a duration to expend 2.1 MJ (E), while in the control trial subjects rested quietly for the same duration. Fasting blood samples were collected before (baseline) and immediately and 120 minutes after the intervention. Subjects then consumed a meal and stayed in the laboratory for postprandial blood collections. Subjects kept weighed food records for two days preceding the first trial and were requested to replicate their diet exactly two days before the second trial. The subjects were also asked to refrain from alcohol, caffeine, and exercise for the two days before each trial.
Preliminary exercise tests: determination of lactate threshold and VO2 peak The participants were required to cycle on a friction-braked cycle ergometer (Monark 824E, Monark Exercise AB, Sweden). The initial load was set at 60 W and increased by 15 W at the end of each three-minute stage. The participants kept a constant pedal cadence of 60 rpm. During the last minute of each three-
minute stage, heart rate was determined (Favor, Polar Electro, Kempele, Finland), expired gas was collected and analysed for VO2 and VCO2 via an online gas analysis system (Oxycon-gamma, Mijnhardt B.V, Holland), and a fingertip capillary blood sample was taken in order to determine lactate concentration by using Lactate Pro (Arkray, Japan). When blood lactate concentration displayed a visually increased breakpoint, a further two stages were undertaken. On cessation of blood sampling, the 15-W increments continued every minute until volitional exhaustion and determination of V˙ O2 peak. LT was confirmed using linear regression analysis according to the intersection of the two bestfitting lines.
Main trials On the experimental days subjects attended the laboratory after a 12-hour fast, where a cannula (Veflon 18G, Becton Dickinson Ltd, Helsingborg, Sweden) was inserted into an antecubital vein and a three-way stopcock (Connecta Plus, Becton Dickinson, Helsinborg, Sweden) was connected to the cannula. After 10 minutes, a baseline blood sample was collected. Subjects then either exercised on a friction-braked cycle ergometer (Monark 824E, Monark Exercise AB, Sweden) at 90 % LT for the duration of 57 ± 3 minutes to expend 2.1 MJ (exercise trial) or rested quietly for the same duration (control trial). Calculations of the duration of exercise sessions to expend ~2.1 MJ were done by using indirect calorimetry equations [33] and individual relationships between VO2 and VCO2 and work load obtained during preliminary exercise tests. Blood samples were collected immediately and 120 minutes after the intervention. Subjects then consumed a meal and stayed in the laboratory for postprandial blood collection at 30, 120 and 180 minutes. The meal provided was isocaloric to the individual’s habitual lunch and provided 3.9 ± 0.69 MJ. It consisted of a chocolate bar (Mars, Slough, UK) and a meal replacement (Complan, H. J. Heinz Co. Ltd., Hayes, UK) mixed with semi- skimmed milk. The amount of Complan powder to be provided and the volume of milk to be added were calculated by taking into consideration the fact that the energy content of the chocolate bar was ~1176 kJ and that 1 g of Complan powder mixed with 3.5 ml of semi-skimmed milk resulted in an energy content of 25 kJ/g.
Estimation of energy intake in habitual lunch For the determination of energy intake in their habitual lunch, subjects were asked to record their lunch for three consecutive days. An experienced nutritionist inspected their records to ensure that they were completed and that sufficient detail had been recorded. The dietary records were analysed using a computerised version of the food composition tables (Diet 5, Robert Gordon University, Aberdeen, UK) [34].
Anthropometry Height and body mass measurements were made using standard procedures. Skinfold thickness was measured using callipers (Holtain, UK) at four sites (triceps, subscapular, biceps, suprailiac), and their sum was used to estimate percentage body fat using the equations of Durnin and Womersley [35].
Blood preparation and plasma analysis For IL-6, insulin, and leptin analyses, venous blood was collected in pre-chilled EDTA vacutainers, and for ghrelin analysis blood was placed into pre-chilled vacutainers containing EDTA and aprotinin (0.6 TIU/ml of blood) to inhibit the activity of pro-
Malkova D et al. Ghrelin and Appetite Following Exercise … Horm Metab Res 2008; 40: 410–415
412 Humans, Clinical teinases. Plasma was separated by centrifugation and stored at − 70 ° C until analysis. Commercially available enzyme immunoassays were used for the analysis of plasma ghrelin (Phoenix Pharmaceuticals, California, USA), IL-6 (R&D Systems, Minneapolis, USA), and insulin (Mercodia, Uppsala, Sweden). Leptin concentration was analysed by radioimmunoassay. All samples for each subject were analysed in the same run and performed in duplicate. The within-assay coefficients of variation were < 4 % for IL-6, leptin, and insulin and < 10 % for ghrelin over the measured concentration range.
Measurement of the drive to eat The visual analogue scales (VAS) were used to evaluate the drive to eat, with subjects reporting ratings for hunger, desire to eat, prospective food consumption, satiety, and fullness [36]. The present VAS were horizontal lines (100 mm long), unbroken and unmarked except for word anchors at either end that describe extremes of the drive to eat. The subjects were instructed to mark the scale with a vertical line at a point that most accurately reflected the intensity of their appetite feeling at that moment in time.
Table 1 Baseline values of plasma ghrelin, IL-6, leptin, insulin, and appetite measures in the control and exercise trials (values are mean ± SE) Parameter
Control
Exercise
ghrelin (pg/ml) IL-6 (pg/ml) leptin (ng/ml) insulin ( U/ml) hunger (mm) desire to eat (mm) PFC (mm) fullness (mm)
676 ± 58 1.3 ± 0.3 4.4 ± 1.1 6.1 ± 0.9 38 ± 9 41 ± 10 67 ± 7 28 ± 8
645 ± 52 1.4 ± 0.4 3.3 ± 6.9 5.2 ± 0.5 39 ± 9 51 ± 7 69 ± 6 30 ± 5
PFC = Prospective food consumption
A
C
B
D
Statistical analysis Results are shown as means ± SE. Baseline data were compared by paired t-test, and then a two-way ANOVA with repeated measures was used on post-intervention responses to determine the effect of trial and time. Two-way ANOVA with repeated measures was also used to compare differences in the preprandial and postprandial period separately. Associations between variables were assessed by Pearson’s product-moment correlations. This was applied to baseline data and to the time-averaged concentrations of the post-intervention period (defined as the trapezium rulederived areas under the concentration vs. time curve, divided by the duration of the observation in the corresponding period). The level of significance was set at p < 0.05. Statistical analyses were performed using Statistica (version 6, Stat Soft Inc., Tulsa, Oklahoma) and SPSS (version 11).
Results & Responses of plasma ghrelin, leptin, insulin, and IL-6 Baseline concentrations of plasma ghrelin, IL-6, insulin, and leptin were not different between the control and exercise trials (Table 1). The post-intervention concentration of plasma ghrelin was significantly lower (p < 0.05) and the concentration of IL-6 higher (p < 0.05) in the exercise than in the control trial (䊉䉴 Fig. 1A, B). When preprandial and postprandial responses of ghrelin and IL-6 were considered separately, the difference in concentration of IL-6 between trials was significant (p < 0.05) only in the preprandial state, while the concentration of ghrelin differed significantly (p < 0.05) only in the postprandial state (䊉䉴 Fig. 1A, B). Post-intervention concentration of plasma leptin tended to be lower (p = 0.06) in the exercise than in the control trial (䊉䉴 Fig. 1C), and responses of insulin were not different between the control and exercise trials (䊉䉴 Fig. 1D). Over time, the plasma concentration of ghrelin, IL-6, insulin, and leptin did not differ in the preprandial state (䊉䉴 Fig. 1A–D). Nor
Malkova D et al. Ghrelin and Appetite Following Exercise … Horm Metab Res 2008; 40: 410–415
Fig. 1 Plasma concentration of ghrelin (A), IL-6 (B), leptin (C) and insulin (D) during preprandial and postprandial periods in the exercise and control trials. Meal consumption is indicated by arrows. Values are means ± SE for 11 men. Significant difference (p < 0.05) between trials over * the post-intervention, a the postprandial, and b the preprandial periods.
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Table 2 Pearson product moment correlations of ghrelin with IL-6, insulin, and leptin for baseline and time-averaged concentrations of the postintervention period in the control and exercise trials
A
Parameter insulin baseline post-intervention IL-6 baseline post-intervention leptin baseline post-intervention
Ghrelin Control
Exercise
− 0.69* − 0.65*
− 0.61* 0.33
0.14 − 0.21
− 0.22 − 0.64*
− 0.41 − 0.60
− 0.32 − 0.57
*p < 0.05 significant correlation between relevant variables
Correlations of ghrelin with insulin, IL-6, leptin, and appetite scores
B
At baseline, the concentration of ghrelin correlated negatively with the concentration of insulin (p < 0.05) in both trials (Table 2). In the post-intervention period, a significant negative correlation was found between time-averaged concentrations of ghrelin and insulin (p < 0.05) in the control trial and time-averaged concentrations of ghrelin and IL-6 (p < 0.05) in the exercise trial (Table 2). In the post-intervention period, time-averaged concentration of ghrelin also tended to correlate negatively with time-averaged concentration of leptin in both the control (p = 0.07) and exercise (p = 0.07) trials (Table 2). No significant associations of plasma ghrelin with appetite scores were noted.
Discussion & Fig. 2 Hunger (A) and desire to eat (B) during the preprandial and postprandial periods in the exercise and control trials. Meal consumption is indicated by arrows. Values are means ± SE for 11 men. aSignificant difference (p < 0.05) between trials over the postprandial period.
were changes in plasma concentration of IL-6 (䊉䉴 Fig. 1B) and leptin (䊉䉴 Fig. 1C) significant over time in the postprandial state. After the meal consumption, the concentration of ghrelin fell significantly (p < 0.05) in both trials, but the duration of postprandial ghrelin suppression was longer in the control trial (䊉䉴 Fig. 1A). Changes in postprandial insulin concentration with time were similar in both trials (䊉䉴 Fig. 1D).
Responses of appetite measures Baseline scores of hunger, desire to eat, prospective food consumption, and fullness were not different between the control and exercise trials (Table 1). Post-intervention responses of appetite measures also were not different between the control and exercise trials. However, when preprandial and postprandial responses of appetite measures were considered separately, postprandial responses of hunger and desire to eat were significantly higher (p < 0.05) in the exercise trial compared with the control trial (䊉䉴 Fig. 2A, B). As expected, a significant effect of the meal was observed (p < 0.01), indicating a decrease in hunger, desire to eat, and prospective food consumption and an increase in fullness following the meal.
This study shows that when estimated for a duration of five hours, the plasma concentration of total ghrelin in healthy adult males was lower after a single exercise session than after resting conditions. Notable was the finding that the difference in ghrelin concentration seen between exercise and control conditions was related to the difference in the response to the meal given two hours after the completion of the intervention. Despite an exercise-induced reduction in the concentration of postprandial ghrelin, hunger and the desire to eat in the postprandial state were higher in the exercise trial than in the control trial. These findings contrast with the regulatory role of ghrelin suggested by intravenous administration studies in which ghrelin modified appetite sensations in a dose-dependent manner [6, 15] and implies that during later hours of post-exercise recovery coinciding with the postprandial state, appetite regulation may be mediated by the action of factors other than ghrelin. Our finding that plasma total ghrelin concentrations during a recovery period lasting for five hours were significantly lower in the exercise than the control trial is similar to the recent report of Broom et al. [27], which showed that concentrations of acylated ghrelin measured for eight hours after running were lower than those during the same period after control conditions. Separate consideration of preprandial and postprandial data, however, revealed that the responses of total and acylated ghrelin in these two studies were similar in the postprandial state but not during the preprandial state, which coincided with the first two hours of the post-exercise recovery. In our study suppression of total ghrelin was seen only during the postpran-
Malkova D et al. Ghrelin and Appetite Following Exercise … Horm Metab Res 2008; 40: 410–415
414 Humans, Clinical dial period, while in the study of Broom et al. [27] exerciseinduced suppression of acylated ghrelin was evident in both the preprandial and postprandial periods. This finding suggests that mechanisms by which total and acylated ghrelin are modified either immediately or up two hours after exercise may be different. On the other hand, a recent study in which total ghrelin measurements during two hours of post-exercise recovery were more frequent than in our study provided evidence of an acute decrease in total ghrelin after a standardised maximal exercise test [26]. As in the case of our study, the above study [26] had no measurements of acylated ghrelin, and the study of Broom et al. [27] had no measurements on total ghrelin; therefore, the extent of variations between responses of total and acylated ghrelin to exercise remains unclear. Although acute suppression of appetite could be expected during and for a short duration after moderate-intensity exercise [19, 27, 37, 38], during the first two hours of the post-exercise recovery in the current study, appetite scores did not differ between the control and exercise trials. Because the suppression of hunger is brief and in some studies returned to control values within 30 minutes [19], it could be argued that our ability to detect the suppression was limited by the low frequency of appetite measurements. At the same time, it should be noted that exercise-induced acute suppression of appetite is not a universal finding and that immediate effects of exercise on appetite also were not found in other studies [39–41]. Therefore, differences in exercise intensity, duration, and exercise-induced energy expenditure also may be responsible for these conflicting results. Indeed, in this study the exercise intensity and the energy expended over the whole exercise session were lower than in some of the studies in which post-exercise suppression of appetite was reported [27, 37, 38]. Although in our study appetite measures were not different between the two trials during the first two hours of the postintervention observation, postprandial hunger and desire to eat measured in response to a test meal consumed two hours after an exercise session were higher in the exercise trial. A tendency toward exercise-induced increases in appetite during the later hours of post-exercise recovery coinciding with postprandial state also was found by Broom et al. [27] and during a meal-tolerance test conducted after the last exercise session of a five-day exercise training program [23]. Thus, it seems that exerciseinduced energy deficits may be maintained during early but not later stages of the post-exercise recovery. This study is one of very few studies in which post-exercise measurements of appetite and ghrelin were conducted under the same experimental conditions, and thus it investigates how ghrelin and exercise interplay to impact on appetite [19, 23, 27]. We found that in the preprandial state neither appetite nor ghrelin was influenced by the exercise session. Thus, our preprandial data cannot be compared with previous evidence suggesting that during the early hours of post-exercise recovery, changes in appetite may be predicted by changes in acylated ghrelin [23, 27] but not total ghrelin [19]. Our postprandial findings suggest that the changes in appetite seen during the later stages of the post-exercise recovery coinciding with postprandial state cannot be explained by changes in total ghrelin. We appreciate that total ghrelin includes both acylated and nonacylated ghrelin [4] and that the nonacylated form of ghrelin may be unimportant in appetite regulation [23], and we admit that the lack of acylated ghrelin measurements limits the interpretation of our results. At the same time, we note that the post-
prandial findings of this study are very similar to the postprandial findings of the recent study [27] in which acylated ghrelin and appetite responses to exercise and consecutive meal were measured for a duration of eight hours. As expected [42], the post-intervention concentration of IL-6 was higher in the exercise trial than in the control trial. However, despite the suggestion that IL-6 may be one of the signals generated by the exercising body that feeds back to the brain to regulate central neuropeptide systems involved in the regulation of energy homeostasis [32], post-intervention appetite scores were not different between the two trials, and postprandial hunger and desire to eat were higher in the exercise trial. Thus, the expected appetite-suppressive role of IL-6 during postexercise recovery has not been confirmed by this study. Further studies are required to determine whether exercise-induced increases in IL-6 have a role in appetite regulation after exercise sessions with different intensities, durations, and energy expenditures. In the current study changes in plasma ghrelin occur in the absence of any change in plasma insulin. This is consistent with the findings of Weickert [43] but contrary to the suggestions implicating insulin in the regulation of ghrelin secretion [29, 30]. The analysis of correlation data between insulin and ghrelin, however, points to the speculation that, under the conditions of this experiment, the regulatory role of insulin was diminished only in the exercise trial. This may be due to the release of exercise-related hormones and metabolites, including increased secretion of IL-6. We found that the exercise-induced reduction in the post-intervention concentration of plasma ghrelin coincided with a significant increase in the concentration of IL-6 and that time-averaged concentrations of ghrelin correlated negatively with concentrations of IL-6 during the post-exercise period. At the same time, we appreciate that regardless of the report allocating a role for IL-6 in the modification of ghrelin secretion under conditions of increased fasting [31], the correlations between ghrelin and IL-6 did not show a causal relation. In this study, the increased suppression of ghrelin at the postprandial nadir seen in the exercise trial was followed by accelerated ghrelin rebound. Thus, future human studies aiming to understand how exercise and ghrelin interplay to impact appetite and thus energy balance may benefit from consideration of the changes over an extended time scale. Indeed, in a recent study conducted on horses, plasma ghrelin concentrations were lower 30 minutes prior to and 15 minutes after a test meal given approximately three hours after the completion of exercise but were higher 12 hours post-exercise compared with control [44]. In summary, despite an exercise-induced reduction in postintervention and postprandial concentrations of plasma ghrelin, the postprandial response of hunger and desire to eat was higher after an exercise session than after resting conditions. Thus, an exercise-induced increase in appetite during the later stages of recovery coinciding with postprandial state cannot be explained by changes in the plasma concentration of total ghrelin.
Acknowledgments & The authors would like to thank the Synergy Fund of Strathclyde and Glasgow Universities.
Malkova D et al. Ghrelin and Appetite Following Exercise … Horm Metab Res 2008; 40: 410–415
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Malkova D et al. Ghrelin and Appetite Following Exercise … Horm Metab Res 2008; 40: 410–415