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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-1028
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 2 648-654
Copyright © 2007 by The Endocrine Society

Regulation of Appetite in Lean and Obese Adolescents after Exercise: Role of Acylated and Desacyl Ghrelin

Kerry J. Mackelvie, Graydon S. Meneilly, Dariush Elahi, Alfred C. K. Wong, Susan I. Barr and Jean-Pierre Chanoine

Endocrinology and Diabetes Unit, British Columbia’s Children’s Hospital (K.J.M., A.C.K.W., J.-P.C.) and Departments of Medicine (G.S.M.) and Food, Nutrition, and Health (S.I.B.), University of British Columbia, Vancouver, Canada; and Department of Surgery (D.E.), Johns Hopkins Medical School, Baltimore, Maryland

Address all correspondence and requests for reprints to: Jean-Pierre Chanoine, M.D., Ph.D., Endocrinology and Diabetes Unit, Room K4-212, British Columbia’s Children’s Hospital, 4480 Oak Street, Vancouver, British Columbia, Canada V6H 3V4. E-mail: jchanoine{at}cw.bc.ca.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Increased physical activity is an integral part of weight loss programs in adolescents. We hypothesized that exercise could affect appetite-regulating hormones and the subjective desire to eat, which could partly explain the poor success rate of the existing interventions.

Objective: The objective of this study was to investigate prospectively the effects of exercise on acylated ghrelin (AG) and desacyl ghrelin (DG) concentrations and on appetite.

Setting: The setting for this study was a tertiary care center.

Participants: Normal-weight [NW; body mass index (mean ± SE), 20.7 ± 0.5 kg/m2] and overweight (OW; body mass index, 32.4 ± 1.7) male adolescents (n = 17/group, age 15.3 ± 0.2 yr) were studied.

Intervention: Those studied participated in 5 consecutive days of aerobic exercise (1 h/d).

Main Outcome: Changes in AG and DG concentrations and in appetite during a test meal were studied.

Results: Exercise did not significantly affect insulin sensitivity or body weight. Fasting total (AG and DG) ghrelin concentrations were lower in OW (600 ± 33 pg/ml) compared with NW (764 ± 33 pg/ml, P < 0.05) boys and were not affected by exercise. In contrast, there was a differential effect of exercise on both AG and DG (P ≤ 0.019). AG significantly increased after exercise, and this increase was greater in NW compared with OW adolescents (P < 0.05). Higher AG concentrations were correlated with an increase in markers of appetite (P < 0.05).

Conclusion: Exercise differentially affects AG and DG in NW and OW male adolescents. Our data suggest that total ghrelin does not adequately reflect AG and DG concentrations and that the influence of exercise-induced hormonal changes should be considered to ensure success in weight management.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE TREATMENT OF adolescent obesity is classically based on three approaches (decreased inactivity, improved diet, and long-lasting lifestyle changes) (1) that are implemented indiscriminately in all subjects. Perhaps unsurprisingly, the success rate of these interventions is poor, and few obese adolescents achieve meaningful weight (fat) reduction at 1 yr postintervention. An additional issue in pediatric medicine is that adolescence is a transition period characterized by profound hormonal changes and critical for the later development of metabolic complications (2).

Ghrelin is an orexigenic hormone that is secreted primarily by the fundus of the stomach and circulates as both acylated and desacyl forms. Exogenous administration of acylated ghrelin (AG) [but not of desacyl ghrelin (DG)] stimulates appetite. This effect is mediated through the GH secretagogue receptor 1a (GHS-R1a) and depends upon the n-octanoyl acylation of ghrelin. In contrast, administration of both AG and DG promote adipogenesis through GHS-R1a-independent pathways that remain to be characterized (3). Thus, both forms of the hormone potentially play a role in energy balance. The physiological role of endogenous ghrelin remains a matter of debate. Ghrelin concentrations increase with fasting and decrease after caloric intake (4, 5), suggesting that it may play a role in hunger and meal initiation (4, 6). In contrast, ghrelin concentrations are decreased in obese adolescents (5) and adults (7) [an effect potentially mediated by hyperinsulinism (8, 9)], making a role of ghrelin in the etiology of obesity unlikely. Ghrelin concentrations increase back toward normal values after weight loss (7, 10), a change that could potentially drive the weight regain experienced by many obese subjects after weight loss.

A better understanding of the effects of therapeutic interventions, such as increased physical activity, on hormonal determinants of appetite control is arguably a key step toward proposing more effective therapeutic approaches. We hypothesized that increased physical activity would affect plasma concentrations of AG as well as the subjective desire to eat in normal-weight (NW) and at-risk for overweight/overweight (OW) male adolescents, which could at least partly explain the poor results of the existing interventions for the treatment of weight excess. To this end, we investigated the changes in AG and DG concentrations and in the satiety response to a test meal after 5 consecutive days of supervised aerobic exercise in two groups of NW and OW adolescents.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Design and schedule

Thirty-four (17 NW and 17 OW) adolescent boys participated in a 1-wk, prospective exercise trial that was independent from any weight loss intervention. The study consisted of five supervised, consecutive, daily, 1-h sessions of aerobic exercise. A meal tolerance test was performed 36 h before the first and after the last exercise session. This design was chosen so that only the effect of increased exercise would be tested; hormonal and satiety response would not be influenced by acute, exercise-related stress, and the 5-d exercise training would not significantly affect body weight or insulin sensitivity.

Subjects and screening visit

Inclusion criteria were as follows: body mass index (BMI) between 10th and 80th percentiles (NW) or above 85th percentile (OW) (11); age, 14–18 yr; nonathlete (less than 2 h/wk physical activity outside of school physical education); nonsmoker; and absence of known endocrine disease/type 2 diabetes or medications. The study was approved by the University of British Columbia Ethics Review Board. We received consent for participation from each boy as well as from their legal guardians.

Height and weight (in light clothing without shoes) were measured in duplicate. BMI [weight (kilograms)/height (meters squared)] and Z score (=[BMI of the subject – mean BMI for age and gender]/[SD]) were calculated. Pubertal development was determined through self-assessment (12).

Pre- and postexercise evaluations

Boys were admitted between 0730 and 0830 h after a 12-h fast. Weight was measured, and an iv catheter was placed. After baseline samples were drawn, subjects consumed, over 10 min, a liquid mixed meal at 40 g carbohydrate/m2 body surface area (Boost High Protein, Mead Johnson, Ottawa, Ontario, Canada) (1 kcal/ml, 20% fat, 55% carbohydrates, 25% protein). Blood was drawn for hormone, nonesterified fatty acids (NEFAs), and glucose determinations at –10, 0, 30, 60, 90, 120, 180, and 240 min. At the time of each blood sample, subjects were asked to do appetite ratings by responding to four questions on: 1) hunger, 2) fullness, 3) desire to eat, and 4) prospective food consumption. For each question, subjects responded by placing a mark on a 100-mm visual analog scale (VAS) as described previously (5).

Blood samples were kept on ice until centrifugation (4 C), and aliquots of plasma were stored at –80 C for subsequent batch analysis. For ghrelin, 50 µl phenylmethane-sulfonylfloride (10 mg/ml solution, Sigma, Oakville, Ontario, Canada), and 50 µl 1 N hydrochloric acid was added to each milliliter of plasma immediately after centrifugation. Total (AG + DG) ghrelin (no. GHRT-89HK, Linco Research, St. Charles, MO) and AG (no. GHRA-88HK, Linco) were determined at each time point by RIA [intraassay coefficient of variation (CV) < 10%]. The concentration of DG was calculated by substraction (total ghrelin – AG).

Plasma testosterone (RIA, intraassay CV < 8.1%, DSL-4100, Diagnostic Systems Laboratories, Webster, TX), IGF-I concentrations (ELISA, intraassay CV < 7.1%, DSL-5600), and high-density lipoprotein (HDL)-cholesterol (enzymatic method, DF48, Dade Behring, Mississauga, Ontario, Canada) were determined at baseline in the same assay. NEFA (enzymatic method, 994-75409 NEFA C, Wako, Richmond, VA) and insulin (ultrasensitive chemiluminescent immunoassay, combined intra- and interassay CV < 5.6%, Beckman Coulter, Fullerton, CA) were determined at all time points. Except for insulin and NEFA, all hormonal assays were performed in duplicate. Plasma glucose was measured by the standard automated enzymatic method. The homeostasis model assessment (HOMA) index [fasting plasma glucose (millimoles per liter) x fasting plasma insulin (microunits per milliliter/22.5)] was used to evaluate insulin sensitivity (13).

Exercise sessions

Exercise intensity was adjusted as tolerated to achieve a heart rate in a range between 65 and 75% of the maximum heart rate reserve (MHRR; 65% MHRR = [{maximum heart rate – resting heart rate} x 0.65] + resting heart rate) (maximum heart rate = 220 beats per minute (bpm) – age (years) and resting heart rate = the average from a 10-min resting session). Each day, boys chose their preferred mode of exercise (walking or jogging on treadmill, cycling, or step climber) under supervision by a fitness specialist.

Statistical analysis

Data are expressed as mean ± SE. The number of subjects in each group (n = 17) was calculated to detect a 15% difference in total ghrelin concentrations pre- and postexercise ({alpha} = 0.05, power 0.8) based on previous data obtained in NW and OW adolescent girls (5). We used independent Student’s t tests to compare baseline descriptive characteristics between NW and OW boys. We examined main effects [group (NW vs. OW), time (pre- vs. postexercise)] and their interaction using repeated measures ANOVA, comparing preexercise and postexercise fasting (premeal), 30, 60, and 90 min (postmeal), and area under the curve (AUC) values for glucose, hormones, lipids, and appetite ratings from the VAS. AUC was determined using the trapezoidal rule. We used linear regression analysis to examine the relationships among hormonal/lipid concentrations and BMI Z score, insulin, HOMA, and hunger after controlling for clinically relevant parameters as appropriate. Data were analyzed with SPSS version 11.0 (2001–2003, SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline characteristics of the subjects

All 34 boys completed the study. One OW boy missed one exercise session because he was feeling unwell. On average, the chosen modes of exercise were treadmill walking/slow jogging (35% of time), upright bicycle (38%), reclined bicycle (15%), and stair climber (12%).

Baseline characteristics are reported in Table 1Go. Boys in both groups were mostly in the mid to late stages of puberty (Tanner pubic hair stages 2–5) with 60% of NW boys and 70% of OW in Tanner stage 4, respectively.


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  		TABLE 1. Characteristics of NW and OW male adolescents

 
Effect of exercise intervention

Physical characteristics. After the 5 d of exercise, there was a nonsignificant weight decrease in NW (–0.2 ± 0.2 kg) and OW (–0.7 ± 0.4 kg) adolescents. Systolic (–6 ± 2 mm Hg) and diastolic (–3 ± 1 mm Hg) blood pressures decreased similarly in both groups (P < 0.05).

Glucose, insulin, NEFA, and HDL-cholesterol. Preexercise fasting glucose concentrations were similar in NW and OW subjects and were not affected by exercise. AUC for glucose and insulin, fasting and 30-min insulin concentrations and HOMA were significantly higher in OW than NW. Exercise caused statistically significant increases in glucose at 30 min (peak) and in glucose AUC that were similar in both groups. Fasting plasma NEFA concentrations were higher in OW compared with NW subjects throughout the liquid meal test (P = 0.001) and decreased in response to the liquid meal (P < 0.001, nadir at 120 min). Overall, NEFA concentrations were higher after exercise (P = 0.048), and this change was similar in NW and OW subjects. Fasting HDL-cholesterol concentrations were similar in NW and OW subjects and were not affected by exercise (Table 2Go).


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  		TABLE 2. Baseline (preexercise) and final (postexercise) plasma concentrations of glucose and insulin in NW and OW male adolescents

 
Ghrelin

Total ghrelin. Preexercise total ghrelin concentrations were significantly lower in OW compared with NW at all time points (all P < 0.02) (Fig. 1AGo). They decreased from 764 ± 33 pg/ml (235 ± 10 pmol/liter) at fasting to 609 ± 26 pg/ml (188 ± 8 pmol/liter) 90 min after the liquid meal in NW subjects and from 600 ± 33 pg/ml (185 ± 10 pmol/liter) to 530 ± 20 pg/ml (163 ± 6 pmol/liter) in OW subjects. Total ghrelin concentrations were unaffected by exercise. The mean ± SE of individual decreases in total ghrelin concentrations from fasting to nadir was greater in NW (–183 ± 17 pg/ml or –56 ± 5 pmol/liter) compared with OW subjects (–119 ± 17 pg/ml or –37 ± 5 pmol/liter, P = 0.011) but was also not affected by exercise (Fig. 1AGo).


Figure 1
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  		FIG. 1. Plasma concentrations of total ghrelin (A), AG (B), and DG (C) before and after exercise over the course of the liquid meal test. AG, picograms/milliliter x 0.2960 = picomoles/liter. DG, picograms/milliliter x 0.308 = picomoles/liter. Data are mean ± SE.

 
AG. Preexercise fasting, 30-, 60-, 90-, and 240-min AG concentrations were similar in OW and NW subjects (Fig. 1BGo). Preexercise AG concentrations at 120 and 180 min were significantly lower in OW compared with NW boys (P ≤ 0.04), and there was a trend toward lower AUC for AG in OW subjects (P = 0.059). AG concentrations decreased similarly in NW and OW subjects from 56 ± 4 pg/ml (17 ± 1 pmol/liter) in the fasting state to 35 ± 3 pg/ml (10 ± 1 pmol/liter) 60 min after the liquid meal (P < 0.001). Exercise caused a statistically significant increase in fasting, 30, 60, and 240 min and in AUC concentrations for AG. However, there was a significant group by intervention interaction (P = 0.016) so that the increase in AG concentrations after exercise was significantly higher in NW compared with OW subjects in the fasting state [+41% (range, –22 to +260%) vs. +10% (range, –23 to +90%), P = 0.03] or tended to be higher at 60 min [+27% (range, –14 to +176%) vs. +3% (range, –42 to +86%), P = 0.085] and for AUC [+ 20% (range, –16 to +105%) vs. no change (range, –20 to +68%), P = 0.059].

DG. Preexercise DG concentrations were significantly lower in OW compared with NW at all time points (all P < 0.02) (Fig. 1CGo). They decreased from 708 ± 34 pg/ml (218 ± 11 pmol/liter) at fasting to 566 ± 24 pg/ml (174 ± 8 pmol/liter) 90 min after the liquid meal in NW subjects and from 544 ± 24 pg/ml (168 ± 7 pmol/liter) to 490 ± 19 pg/ml (151 ± 6 pmol/liter) in OW subjects. There was a significant group x intervention interaction (P = 0.019), suggesting a different effect of exercise on DG in OW and NW subjects. In NW boys, exercise caused a decrease in DG concentrations, contrasting with an increase in OW boys, and this difference was mostly present 2–4 h after the liquid meal (group x time interaction, P = 0.019) (Fig. 1CGo). Accordingly, DG AUC decreased by 3% (range, –15 to +9%) in NW but increased by 4% (range, –9 to +21%) in OW adolescents (P = 0.015). The mean ± SE of individual decreases in DG concentrations from fasting to 90 min was greater in NW (–142 ± 23 pg/ml or –44 ± 7 pmol/liter) compared with OW subjects (–54 ± 16 pg/ml or –17 ± 5 pmol/liter, P = 0.003) but was not affected by exercise.

Fasting DG and AG concentrations were positively correlated both before [r = 0.42, 95% confidence interval (CI) (0.10–0.66), P = 0.012] and after [r = 0.66, 95% CI (0.42–0.82), P < 0.001] exercise. There was a negative correlation between fasting and AUC for DG concentrations and BMI Z score [r ≤ –0.35, 95% CI (–0.62 to –0.01), P ≤ 0.043] or HOMA [r ≤ –0.48, 95% CI (–0.70 to –0.17), P ≤ 0.04] both before and after exercise. There was also a negative correlation between AUC for AG and HOMA before and after exercise [r < –0.45, 95% CI (–0.69 to –0.13), P = 0.008].

Testosterone and IGF-I. We also investigated whether the changes in AG/DG after exercise were associated with changes in testosterone or IGF-I. Preexercise testosterone concentrations were lower in OW (86 ± 46 ng/dl or 3.0 ± 1.6 nmol/liter) compared with NW (141 ± 35 ng/dl or 4.9 ± 1.2 nmol/liter, P < 0.001) subjects. After exercise, testosterone concentrations increased by 10 ± 6 ng/dl (0.33 ± 0.22 nmol/liter) in NW subjects but further decreased by 10 ± 5 ng/dl (0.34 ± 0.18 nmol/liter) in OW subjects (group x intervention effect, P = 0.02, Fig. 2AGo). This difference persisted after controlling for Tanner stage. There was a negative correlation between the changes in testosterone concentrations and the changes in the liquid meal-induced decrease in DG between 0 and 90 min. In other words, subjects with a testosterone increase after exercise experienced less postmeal decrease in DG [r = –0.40, 95% CI (–0.65 to –0.07), P = 0.02, Fig. 2BGo].


Figure 2
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  		FIG. 2. A, Effect of exercise on testosterone concentrations in NW and OW subjects. B, Relationship between changes in fasting plasma testosterone and changes in meal induced-decrease in DG between 0 and 90 min after ingestion of the liquid meal before and after exercise in NW and OW boys. Testosterone, nanograms per deciliter x 0.0347 = nanomoles per liter.

 
Preexercise IGF-I concentrations were similar in OW compared with NW subjects (618 ± 205 µg/liter or 81 ± 27 nmol/liter). Overall, exercise caused a decrease in IGF-I concentrations (P = 0.01) that was significantly greater in OW (–79 ± 25 µg/liter or –10 ± 3 nmol/liter) subjects compared with NW subjects (–6 ± 20 µg/liter or –1 ± 3 nmol/liter) (group by intervention effect, P = 0.03) and persisted after adjustment for height SDS.

Appetite. Overall, NW subjects expressed greater hunger (fasting and AUC), desire to eat (fasting, 30 min and AUC), and prospective food consumption (fasting and AUC) than OW subjects both before and after exercise (all P < 0.05), whereas the sensation of fullness was similar. Exercise tended to decrease fullness (P = 0.055) similarly in NW and OW adolescents.

Fasting hunger [r > 0.48, 95% CI (0.17–0.70), P < 0.004] and desire to eat [r > 0.55, 95% CI (0.26–0.75), P < 0.001] were positively associated with fasting and AUC for total ghrelin/DG but not with AG concentrations. This relationship was independent from fasting insulin or NEFA concentrations.

We analyzed the relationship between changes in ghrelin and changes in markers of appetite after exercise. Overall, changes in AG, and to a lesser extent in DG, concentrations correlated positively with changes in markers of appetite; the greater the increase in ghrelin, the greater the increase in appetite. Changes in total ghrelin did not significantly predict changes in appetite.

We found a positive correlation between changes in plasma concentrations of AG (but not of total ghrelin or DG) at 30 min and hunger at 30 min [r = 0.43, 95% CI (0.10–0.67), P = 0.013, Fig. 3Go], desire to eat at 30 [r = 0.42, 95% CI (0.10–0.67), P = 0.018] and 60 min [r = 0.57, 95% CI (0.28–0.76), P = 0.001], and AUC for prospective food consumption [r = 0.36, 95% CI (0.02–0.63), P = 0.046]. We also found positive correlations between changes in fasting DG concentrations and changes in desire to eat 30 and 60 min after liquid meal ingestion [r > 0.36, 95% CI (0.01–0.62), P ≤ 0.04].


Figure 3
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  		FIG. 3. Relationship between changes in hunger at 30 min and changes in total ghrelin (A), AG (B), and DG (C) concentrations before and after exercise 30 min after administration of the liquid test meal. One NW subject did not understand the appetite questionnaire at the first visit, and the change in his ratings (>3 SD above the mean) was excluded from the analysis (arrow).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We show that daily exercise for 5 consecutive days is associated with an increase in plasma concentrations of AG that is independent from the acute effect of exercise and from changes in weight or markers of insulin sensitivity. In addition, the increase in AG was more pronounced in NW compared with OW subjects and was associated with an increase in markers of appetite; the greater the increase in ghrelin, the greater the increase in hunger, desire to eat, and decrease in fullness. We also show that exercise differently affects the DG response to a liquid meal.

Similar to our recent work in female adolescents (5) and to pediatric (14, 15) and adult (16, 17) data from the literature, we observed a negative correlation between plasma concentrations of DG and BMI Z score in NW and OW male adolescents. In the present study, plasma concentrations of DG ghrelin were lower in OW compared with NW subjects, whereas AG concentrations were only lower toward the end of the meal test. This contrasts with adult studies in which fasting concentrations of AG were 56–66% lower in obese compared with lean subjects (17, 18). However, Vivenza et al. (19) only observed a 17% decrease in obese compared with lean peripubertal subjects, suggesting that the relationship between AG concentrations and BMI changes is different in adult and pediatric populations. DG and AG concentrations were also negatively correlated with markers of insulin resistance such as HOMA. These data are consistent with our previous report in female adolescents (5) and with the hypothesis that insulin resistance plays a causal role in the lower ghrelin concentrations observed in young obese subjects (8, 20).

Our study is the first to compare the effect of physical activity on AG and DG in NW and OW adolescents. This point is important because AG represents less than 10% of total (AG + DG) ghrelin. In addition, although AG activates GHS-R1a and stimulates appetite, DG does not activate GHS-R1a but could potentially affect adipogenesis and therefore energy balance through a GHS-R1a-independent mechanism (3). Most (21, 22, 23, 24, 25) but not all (26) authors reported that total ghrelin concentrations were unaffected by short-term exercise in lean healthy adults and that ghrelin does not mediate the physiological exercise-induced GH secretion. In contrast, some (27, 28) but not all (29) authors observed an increase in total ghrelin concentrations with long-term exercise, but only when it is associated with weight loss and/or improved insulin sensitivity. The duration of our study was short enough not to affect insulin sensitivity and weight. In addition, we waited 36 h between the last exercise session and the second meal test so that ghrelin concentrations would not be affected by the acute effects of exercise. Therefore, the lack of a specific effect of exercise on total ghrelin concentrations is in agreement with the above studies. In contrast, we observed differential changes in AG and DG levels in NW and OW subjects, suggesting that the measure of total ghrelin concentrations does not adequately capture changes in AG and DG.

The question of whether exercise, independent of its longer term effects on energy balance, influences appetite has long been studied. A recent review of the current evidence around the effect of short and long-term physical activity on appetite showed that there tends to be little compensation, in terms of energy intake, for exercise sustained over 1–16 d. Beyond this, compensators and noncompensators emerge, in that some people tend to increase their energy intake, and therefore maintain or gain weight, and some tend to maintain their energy intake at preexercise levels and lose weight. The characteristics underpinning differential energy intake compensation are unknown, but individual changes in appetite-related hormones may be one of the factors involved.

To assess the clinical relevance of the observed changes, we examined the relationship between hormonal changes and changes in the subjective markers of appetite. Although exogenous AG increases appetite in both humans and animals, the role of endogenous AG in appetite regulation is less clear (for review, see Ref. 30). Our result that positive changes in AG concentrations after exercise are associated with positive changes of markers of appetite and negative changes in markers of fullness is thus interesting. This is to our knowledge the first study demonstrating a relationship between subjective feeling of appetite and AG. We have previously observed modest positive correlations between markers of appetite and total ghrelin in female adolescents (5). Cummings et al. (4) observed an association between increased total ghrelin concentration and spontaneous meal initiation. In contrast, the same authors found no relationship between the recovery of ghrelin concentrations after a meal and the interval between the meals (31). These discrepant results on the relationship between absolute levels of total ghrelin and appetite markers are not surprising because ghrelin is only one of the many signals that control appetite (32). In addition, there is a wide range of ghrelin concentrations in a normal population, suggesting that circulating ghrelin may represent a set point specific to each individual.

We also observed a differential effect of exercise on DG concentrations in NW and OW subjects, mainly in the late postprandial period. The significance of this result is unclear, but the process of acylation/desacylation of ghrelin could conceivably serve to fine tune energy balance. It is important to note, however, that DG was obtained by subtracting AG from total ghrelin values, and not by direct measure, meaning that changes in AG may be a confounding factor for changes in DG.

Preexercise testosterone concentrations were 39% lower in OW compared with NW adolescents, a finding consistent with the delayed puberty observed in obese male adolescents (33). We observed an increase in testosterone concentrations in NW boys but a further decrease in OW boys after exercise, and these changes were significantly correlated with DG changes; the greater the increase in testosterone, the smaller the postmeal decrease in DG. The effect of exercise on testosterone levels has been largely studied in lean adults, and studies have generally found no change or, similar to our study, an increase in testosterone concentrations (for review, see Ref. 34). To our knowledge, no study has compared the effect of exercise, without weight loss, on testosterone concentrations in adolescents. Circulating total ghrelin decreases with advancing pubertal development (35). Exogenous testosterone decreased total ghrelin concentrations in peripubertal children 10 d after an injection (36), whereas more prolonged testosterone administration had no effect in boys with delayed puberty (37) but increased total ghrelin in hypogonadal adult men (38). Preexercise IGF-I concentrations were similar in NW and OW boys and decreased after exercise in OW boys only. Available data from the literature suggest that IGF-I concentrations remain roughly within the normal range in obese adults (for review, see Ref. 39) and children (40). The effect of exercise on IGF-I concentrations has been variable (for review, see Refs. 34 , 41).

Our study has several limitations. First, we did not try to control energy intake during the 5 d of exercise, nor quantify it. Therefore, whether our results translate into an actual increase in energy intake and whether AG changes are sustained over time remains to be demonstrated. Despite the above limitations, it could be speculated that the increases in AG and the associated increases in appetite markers would limit the effectiveness of exercise-based weight loss programs. However, the increase in AG in OW boys was less marked than in NW boys, suggesting that increases in energy intake (if they actually occur) could be smaller in OW individuals and still consistent with an overall negative energy balance. Second, the duration of our study was short (5 d), and the type of exercise chosen was aerobic. It cannot be ruled out that different exercise programs may have different effects on ghrelin concentrations.

In conclusion, we showed that the response in AG and DG to the early stages of an exercise program differs between NW and OW adolescent boys and that these changes are associated with concomitant changes in the subjective feeling of appetite. These novel data imply that total ghrelin concentrations cannot consistently be used as a surrogate marker for AG or DG concentrations. Our data also raise the possibility that acylation of ghrelin may represent a fine-tuning mechanism that can modulate energy balance by two different mechanisms, appetite and adipogenesis. Although we believe in the important role of exercise in weight loss programs, our data suggest that the influence of exercise-induced hormonal changes should be considered to ensure successful weight management.


   Acknowledgments
 
We acknowledge the support of the Alan McGavin Geriatric Medicine Endowment of the University of British Columbia and the Jack Bell Geriatric Endowment Fund at Vancouver General Hospital. We thank all participants for time and commitment and the Mead Johnson Company for providing the Boost. We are indebted to M. L. Heimon (Eli Lilly, Indianapolis, IN) for his intellectual contribution, and to Leslie MacLean, Heather Macdonald, Kate Reed, Christine Lockhart, and Gail Chin for exercise session supervision and technical assistance.


   Footnotes
 
This work was supported by an operating grant from the Vancouver Foundation. K.J.M. was supported by a postdoctoral fellowship from the Michael Smith Foundation for Health Research.

The authors have nothing to declare.

First Published Online November 21, 2006

Abbreviations: AG, Acylated ghrelin; AUC, area under the curve; BMI, body mass index; bpm, beats per minute; CI, confidence interval; CV, coefficient(s) of variation; DG, desacyl ghrelin; GHS-R1a, GH secretagogue receptor 1a; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; MHRR, maximum heart rate reserve; NEFA, nonesterified fatty acid; NW, normal weight; OW, at risk of overweight/overweight; VAS, visual analog scale.

Received May 12, 2006.

Accepted November 15, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Whitlock EP, Williams SB, Gold R, Smith PR, Shipman SA 2005 Screening and interventions for childhood overweight: a summary of evidence for the US Preventive Services Task Force. Pediatrics 116:e125–e144
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  3. van der Lely AJ, Tschop M, Heiman ML, Ghigo E 2004 Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 25:426–457[Abstract/Free Full Text]
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