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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 9 4729-4733
Copyright © 2004 by The Endocrine Society

The Cholinergic System Controls Ghrelin Release and Ghrelin-Induced Growth Hormone Release in Humans

Christina Maier, Georg Schaller, Barbara Buranyi, Peter Nowotny, Georg Geyer, Michael Wolzt and Anton Luger

Department of Medicine III (C.M., P.N., A.L.), Clinical Division of Endocrinology and Metabolism; Department of Clinical Pharmacology (G.S., M.W.); and Ludwig Boltzmann Institute for Experimental Endocrinology (B.B., G.G., A.L.), Medical University of Vienna, 1090 Vienna, Austria

Address all correspondence and requests for reprints to: Christina Maier, M.D., Department of Medicine III, Clinical Division of Endocrinology and Metabolism, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. E-mail: christina.maier{at}akh-wien.ac.at.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The stomach-derived peptide hormone ghrelin induces appetite and GH release. Several ghrelin actions are possibly mediated and modulated by the central cholinergic system. The aim of this study was to investigate the influence of the unspecific cholinergic antagonist atropine and the acetylcholine esterase inhibitor pyridostigmine, a cholinergic enhancer on ghrelin plasma concentrations and ghrelin-induced GH release. We investigated plasma ghrelin concentrations, ghrelin-induced GH release, and glucose and insulin concentrations after administration of atropine or pyridostigmine, and ghrelin (in two different doses, 0.25 and 1 µg/kg body weight), alone and in combination in a randomized, double-blind, placebo-controlled, crossover study design on 12 young, healthy male volunteers.

Atropine alone significantly reduced fasting ghrelin levels by 25%, whereas under pyridostigmine alone ghrelin levels were unaltered. Ghrelin in combination with atropine induced significantly reduced GH concentrations compared with ghrelin administration alone for both ghrelin doses, whereas ghrelin-induced GH peak concentrations and areas under the curve were not enhanced by pyridostigmine treatment. These results suggest that, in humans, fasting ghrelin concentrations might be under cholinergic control and that the cholinergic system appears to modulate ghrelin-induced GH release.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ALTHOUGH IT IS well established that the stomach-derived peptide hormone ghrelin (1, 2) stimulates both appetite and GH release in humans (3) and animals (1, 4), there are still few data on the regulation of ghrelin release itself. One main factor influencing ghrelin plasma concentrations is food intake; shortly after oral glucose load, ghrelin concentrations fall significantly (5). Ghrelin concentrations rise anticipatory to meal initiation in both humans (6) and sheep (7), and it has been suggested that this rise is elicited centrally and mediated via cholinergic pathways and the vagus nerve to the stomach mucosa (7). In vagotomized rats, ghrelin-induced feeding (8, 9) and GH secretion (9) were abolished. In another study (10), baseline ghrelin concentrations and suppression of ghrelin concentrations by nutrient load were unaltered upon vagotomy, but increase of ghrelin levels induced by 48-h food deprivation was abolished completely, and this result was mimicked by the unspecific muscarinic receptor antagonist atropine (ATR) treatment.

The cholinergic system takes also part in the preabsorptive or cephalic phase of insulin release, which is initiated by meal ingestion and abolished by ATR (11).

Somatostatin (SRIF) acts as a functional ghrelin antagonist: SRIF infusion suppresses ghrelin concentrations in humans (12), and the GH-releasing effect of ghrelin is blunted by SRIF infusion in young healthy volunteers (13). It is also thought that SRIF mediates the modulation of GH release by cholinergic pathways (14). In healthy volunteers, muscarinic cholinergic agonists such as pyridostigmine (PD) or pilocarpine potentiate GH response to the GHRH (15, 16) and exercise (17). Furthermore, GH release to various stimuli is suppressed by the specific M1-receptor antagonist pirenzepine (18) as well as by the unspecific muscarinic antagonist ATR, the latter probably acting at a more central level (19, 20).

In a recent study in humans (21), neither PD nor the specific M1-receptor antagonist pirenzepine was able to significantly alter the GH-releasing effect of a high dose (1 µg/kg) of ghrelin. The aim of our study was to further investigate the influence of the cholinergic system on ghrelin-induced GH release, including possible regulation mechanisms at a central level. For this purpose, ATR, a cholinergic antagonist that in contrast to pirenzepine crosses the blood-brain barrier (22), and PD were administered to healthy volunteers either alone or in combination with ghrelin at two different doses. To evaluate possible cholinergic influence on ghrelin secretion, the effect of ATR and PD administration on ghrelin plasma concentrations was determined.


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

Twelve young, healthy male volunteers, aged 27.6 ± 1.1 (mean ± SEM) yr, with a body mass index (BMI) of 24.0 ± 0.5, were studied. All of them were nonsmokers; none of them were taking any medication. The study protocol had been approved by the Ethics Committee of the University of Vienna, and all subjects had given informed consent before study entry.

Study design and schedule

The study was designed as a randomized, double-blind, placebo-controlled, crossover study. For all subjects, six study days (A-F) with at least 3-d washout intervals (mean intervals, 5.9 ± 0.3 d) were scheduled in randomized order: day A, PD (Mestinon; Hoffmann-La Roche, Basel, Switzerland) 120 mg by mouth at time point –60 and placebo (isotonic saline) iv at time point 0; day B, ATR (atropinum sulfuricum, brand name Nycomed; Nycomed, Linz, Austria) 1 mg iv at time point 0 and placebo iv at time point 0; day C, PD at –60 and ghrelin (purchased as sterile, lyophilized powder from Calbiochem-Novabiochem, Läufelingen, CH; purity 99.8%, molecular weight: 3370.9) 0.25 µg/ kg body weight (BW) at 0; day D, ATR at 0 and ghrelin 0.25 µg/ kg BW at 0; day E, PD at –60 and ghrelin 1 µg/ kg BW at 0; and day F, ATR at 0 and ghrelin 1 µg/ kg BW at 0.

Six of the 12 subjects were also tested with the two doses (0.25 and 1 µg/kg, respectively) of ghrelin alone; these additional study days were also randomized.

Ghrelin was dissolved in isotonic saline immediately before injection; volunteers as well as researchers were blinded to ghrelin/placebo dosage.

Tests began in the morning (0830-1100) after a 12-h fasting period; subjects arrived at the same time point for each study day. A plastic cannula was inserted into an antecubital vein, and blood samples were drawn at time points –60 (study days A, C, E) and 0, 15, 30, 45, and 60 (all study days) for measurements of plasma GH, ghrelin, insulin, and blood glucose. Blood pressure (measured on the upper arm) and pulse rate (finger pulse oximetry) were monitored throughout the study period with automated devices and recorded at –60 (study days A, C, E) and 0, 15, 30, 45, and 60 (all study days). An overview of the study schedule is given in Table 1Go.


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  		TABLE 1. Overview of the study schedule

 
Laboratory monitoring

Samples for plasma hormone measurements were centrifuged immediately at 4 C and the supernatants stored at –30 C until analysis.

GH concentrations (in nanograms per milliliter) were measured in duplicate with an immunoradiometric assay (hGh IRMA; DiaSorin, Saluggia, Italy), sensitivity 0.1 ng/ml, both inter- and intra-assay coefficients of variation 4–6%. Cross-reactivity of the assay with the ghrelin used in the study was tested and found to be zero.

Insulin levels (µU/ml) were assayed by a commercially available RIA (Pharmacia-Upjohn, Uppsala, Sweden), and both inter- and intraassay coefficients of variation were 5%.

Plasma ghrelin (femtomoles per milliliter) was measured with a commercial RIA (Peninsula Labs, San Carlos, CA) that uses I-125-labeled bioactive ghrelin as a tracer and polyclonal antibody raised in rabbits against the C-terminal end of human ghrelin. Blood glucose was determined according to standard laboratory procedures.

Statistical analysis

For GH, areas under the curve (AUCs) were calculated from time point 0 to 60 by trapezoidal integration using Origin 5.0 (Microcal, Northampton, MA). GH AUCs and peak levels were compared by one-way ANOVA, followed by multiple t tests with Bonferroni correction using SPSS 11.5 (SPSS Inc., Chicago, IL). Blood pressure, pulse, and ghrelin, insulin, and glucose baseline vs. 15' levels and baseline vs. 30' levels were compared with ANOVA for repeated measures followed by paired Student’s t test for study days A-F and Wilcoxon’s signed rank test for study days G and H. P < 0.05 was considered significant. Results are presented as means ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Effect of ATR and PD on ghrelin plasma concentrations

Ghrelin concentrations at baseline were not different between the study days. ATR administration led to a decrease of ghrelin plasma concentrations that was already statistically significant at time point 15' (baseline, 186.7 ± 17.9 fmol/ml; 15', 159.6 ± 13.6 fmol/ml; P = 0.007) and further decreased to a nadir of 140.9 ± 15.7 fmol/ml at 60'. PD alone led to a small, insignificant rise of ghrelin plasma levels (baseline, 199.4 ± 30.4 fmol/ml; 15', 195.6 ± 14 fmol/ml; P = 0.863) up to 207.3 ± 19 fmol/ml at time point 60'. Ghrelin levels were significantly different between ATR and PD pretreatment at time point 15' (P = 0.033). An overview of ghrelin concentrations with ATR or PD treatment is given in Fig. 1Go.



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  		FIG. 1. ATR treatment (1 mg iv at time point 0, filled circles) promptly and significantly reduces ghrelin plasma levels in 12 fasted, healthy volunteers, whereas ghrelin concentrations remain unaltered after PD (120 mg po at time point –60 min, open squares) treatment.

 
Ghrelin plasma concentrations after two doses of ghrelin

Ghrelin administration at 0.25 µg/ kg led to an increase in circulating ghrelin concentrations with peak values of 634 ± 22.6 fmol/ml. The higher ghrelin dosage (1 µg/ kg) induced peak values of 1959.4 ± 163.5 fmol/ml. ATR or PD treatment did not influence ghrelin plasma concentrations at both dosages.

Effect of ATR and PD on basal and ghrelin-stimulated GH concentrations

GH levels at baseline were comparable for all study days. PD administration alone led to a significant GH elevation compared with ATR administration in both peak values (PD, 6.7 ± 1.2 ng/ml; ATR, 0.15 ± 0.08 ng/ml; Pdiff = 0.002) and AUCs (PD, 194 ± 45.2 ng·min/ml; ATR, 4.6 ± 3.2 ng·min/ml; Pdiff = 0.005; Fig. 2AGo).



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  		FIG. 2. A, PD (120 mg by mouth at time point –60 min) leads to a significant elevation of GH levels, whereas GH concentrations remain unchanged under ATR treatment (1 mg iv at time point 0). Open squares, GH concentrations after PD treatment. Filled circles, GH concentrations after ATR treatment. B, ATR significantly reduces whereas PD does not enhance ghrelin-induced GH release at a ghrelin dose of 0.25 µg/kg BW. C, ATR significantly reduces whereas PD does not enhance ghrelin-induced GH release at a ghrelin dose of 1 µg/kg BW. B and C, Dashed line, GH concentrations after ghrelin (0.25 µg and 1 µg/kg BW). Open squares, GH concentrations after ghrelin + PD (120 mg). Filled circles, GH concentrations after ghrelin + ATR (1 mg).

 
ATR treatment led to GH concentrations significantly different from those induced by ghrelin alone. In the six subjects studied with ghrelin alone, GH concentrations rose to peak values of 40.1 ± 8 ng/ml (0.25 µg/kg) and 64.9 ± 2 ng/ml (1 µg/kg). With PD pretreatment, GH peak values were 41.5 ± 4.8 ng/ml (0.25 µg/kg ghrelin, P vs. ghrelin alone = 1) and 52.8 ± 3.3 ng/ml (1 µg/kg ghrelin, P vs. ghrelin alone = 0.783). With ATR pretreatment, GH peak values were lower at both ghrelin dosages: 21.5 ± 5.2 ng/ml (P vs. ghrelin alone = 0.056) and 35.4 ± 6.5 ng/ml (P vs. ghrelin alone = 0.005; Fig. 2Go, B and C).

Consistent results were obtained when AUCs were compared: AUCs with ghrelin at 0.25 µg/kg BW were 1565.2 ± 409.8 ng·min/ml (ghrelin alone), 1841.4 ± 311.7 ng·min/ml (PD), and 474.9 ± 211 ng·min/ml (ATR) (ATR vs. ghrelin alone, P = 0.02; PD vs. ghrelin alone, P = 1) and AUCs with ghrelin at 1 µg/kg BW were 2906 ± 165.2 ng·min/ml (ghrelin alone), 2568.3 ± 232 ng·min/ml (PD), and 1524.2 ± 311.8 ng·min/ml (ATR), respectively (ATR vs. ghrelin alone, P = 0.011; PD vs. ghrelin alone, P = 0.999). Thus, ATR pretreatment led to significantly lower GH concentrations compared with ghrelin alone. In contrast, PD did not affect GH concentrations.

An overview of GH concentrations at all study days is given in Fig. 2Go.

Effect of ghrelin on insulin and glucose concentrations

Ghrelin administration at both dosages also led to a significant decrease in insulin concentrations at time point 15' vs. baseline accompanied by an increase in blood glucose concentrations, which was not significant with 1 µg/kg BW ghrelin. ATR or PD treatment alone did not significantly change insulin or glucose concentrations. Also, ghrelin-induced changes in insulin levels were not influenced by ATR or PD; the effect on glucose concentrations, however, was more heterogenous. An overview of the glucose and insulin results is given in Table 2Go.


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  		TABLE 2. Glucose and insulin concentrations

 
Effect of ATR and PD on blood pressure and pulse rate

PD administration significantly reduced (baseline 75.5 ± 3.2 min–1 vs. 15' 60.6 ± 2.2 min–1; P < 0.001) and ATR significantly enhanced (baseline 77.2 ± 3.9 min–1 vs. 15' 87.7 ± 4.2 min–1; P = 0.025) pulse rate. ATR did not lead to a significant alteration of systolic (126.7 ± 2.9 mm Hg baseline vs. 125.5 ± 3.4 mm Hg 15'; P = 0.717) or diastolic blood pressure (63.6 ± 3.9 mm Hg baseline vs. 68 ± 3.3 mm Hg 15'; P = 0.18), whereas PD significantly reduced systolic (127.2 ± 3.5 mm Hg baseline vs. 118.5 ± 3.3 mm Hg 15'; P = 0.001) but not diastolic (64 ± 2.4 mm Hg baseline vs. 60.5 ± 3.1 mm Hg 15'; P = 0.149) blood pressure. ATR and PD effects were not significantly influenced by ghrelin treatment.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Cholinergic blockade by ATR after overnight fasting promptly and significantly decreased plasma ghrelin concentrations in the group of young healthy males in this study. The amount of ghrelin decrease upon ATR injection in this group of fasted healthy subjects (25%) was considerable. In a study on 10 healthy humans (with comparable BMI and ghrelin fasting levels), the magnitude of the average decrease in plasma ghrelin from peak to trough was 54% after breakfast (6). In a more recent study (23), however, ghrelin levels decreased only 31% (in lean subjects) and 28% (in obese subjects) upon meal ingestion. Thus, the amount of decrease shown in this study indicates a relevant participation of cholinergic control in preprandial ghrelin secretion from the stomach. Because ghrelin levels have been shown to follow a circadian rhythm, we cannot, in the absence of a placebo group, completely rule out the possibility that the decrease in ghrelin concentrations was induced by a spontaneous diurnal variation, but the time course (15 min after ATR) and the extent of the effect (–25%) strongly suggest that ATR was responsible for the ghrelin drop.

It has been shown that ghrelin levels are decreased by SRIF infusion in humans (12) and that SRIF is produced in the stomach mucosa. Therefore, it would be possible that the effect of ATR on ghrelin release was mediated by gastric SRIF. However, this explanation seems rather unlikely, because it has been shown in rodents that gastric SRIF release is unaffected by vagotomy (24). The observation that PD (which is assumed to act by lowering somatostatinergic tone) was unable to change ghrelin levels suggests that the physiological somatostatinergic tone might not be involved in the regulation of ghrelin concentrations during fasting.

During the preparation for this manuscript, a paper describing the effect of the muscarinic antagonist pirenzepine and PD on ghrelin secretion has been published (25). In this study, pirenzepine reduced ghrelin levels to the same amount as described here. In contrast to our data, PD was able to significantly increase ghrelin concentrations with a maximum at 120 min after PD administration. A possible explanation for this discrepancy could be that in our study ghrelin concentrations, after the 12-h fasting period, might already have reached maximal values at baseline. However, because absolute ghrelin concentrations at baseline were not reported in the paper, a direct comparison is not possible.

In addition to reducing ghrelin plasma concentrations, ATR also significantly reduced ghrelin-induced GH release in this study. In a recent study on young, healthy volunteers (21), no significant effect of manipulation of the cholinergic system with either PD or pirenzepine on the ability of ghrelin to induce GH release was found. Thus, the finding of a significant effect of cholinergic blockade with ATR on ghrelin-induced GH release is in contrast to these data. The fact that we used ATR instead of pirenzepine might account for this discrepancy. ATR, in contrast to pirenzepine, is able to cross the blood-brain barrier. Recently, it has been shown that in vivo the effect of ghrelin on GH release is mediated via the hypothalamic releasing hormone GHRH rather than directly via the pituitary (26, 27). Thus, one possible explanation for the discrepancy between the effectiveness of ATR and the ineffectiveness of pirenzepine would be that the interplay between the cholinergic system and ghrelin occurs at a central level that is not reached by pirenzepine.

This would not explain however why PD was unable to enhance ghrelin-induced GH release, even at a low dose of ghrelin in combination with a PD dose leading to a significant elevation of GH levels when administered alone (Fig. 2AGo). There are several possible explanations for the striking discrepancy between the effectiveness of cholinergic blockade and the inability of cholinergic enhancement to modify ghrelin-induced GH release. According to general belief, the main influence of PD on GH release is via lowering somatostatinergic tone in the median eminence of the hypothalamus (14). It has been shown that SRIF infusion blunts ghrelin-induced GH release (13). Thus, one would expect that upon lowering SRIF influence, ghrelin effect on GH release would be enhanced. Therefore, the results of this and the above-mentioned studies suggest that normal SRIF tone might be too low to control ghrelin actions on GHRH/GH release. Alternatively, the nonadditive effect of ghrelin and PD could be attributed to the fact that both substances act on the same pathway. Indeed, the common view that PD acts mainly via lowering SRIF tone has been challenged by the use of a GHRH antagonist that almost abolished PD-induced GH release in healthy humans (28).

We also measured ghrelin plasma levels after administration of different doses of ghrelin. The peak plasma ghrelin levels (634.6 ± 22.6 fmol/ml) achieved with the lower ghrelin dosage (0.25 µg/ml) were higher than the upper range (447.8 fmol/ml) of fasting ghrelin levels reported in a recent population study in adults using the same RIA for plasma ghrelin determination (29). Thus, it can be assumed that even those plasma levels are supraphysiological for healthy humans and maybe lower doses of ghrelin than the 1 µg/kg used in most studies up to now would be more appropriate for studies on ghrelin physiology.

Ghrelin seems to suppress insulin release from pancreatic ß-cells (30, 31), and it has been shown repeatedly that insulin levels decrease after ghrelin administration in rodents (31) and humans (21, 32). Ghrelin appears also to influence gluconeogenesis in the liver (33). Significant reduction of insulin levels accompanied by elevation of glucose levels at time point 15' was also seen in this study at a ghrelin dose of 0.25 µg/kg BW, whereas at 1 µg/kg ghrelin insulin concentrations were significantly decreased, but glucose concentrations showed only a trend to increase. The interrelation among ghrelin, insulin, and glucose appears to be complex and needs to be studied in a setting with more frequent blood sampling and more ghrelin doses. The time interval of 15 min chosen in this study does not allow drawing conclusions on the actual order of glucose rise and insulin drop.

Taken together, the data from our study provide evidence that interplay exists between ghrelin and the cholinergic system in humans. It has shown that cholinergic blockade with ATR suppresses ghrelin plasma concentrations and modulation of the cholinergic system with ATR, but not PD, influences the ability of different ghrelin dosages to induce GH release.


   Footnotes
 
This work was supported by the Jubiläumsfonds der Österreichischen Nationalbank, project no. 10321.

Abbreviations: ATR, Atropine; AUC, area under the curve; BMI, body mass index; BW, body weight; PD, pyridostigmine; SRIF, somatostatin.

Received April 6, 2004.

Accepted June 16, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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