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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1785
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 2982-2987
Copyright © 2005 by The Endocrine Society

Endogenous Circulating Ghrelin Does Not Mediate Growth Hormone Rhythmicity or Response to Fasting

Anca M. Avram, Craig A. Jaffe, Kathleen V. Symons and Ariel L. Barkan

Division of Endocrinology and Metabolism, University of Michigan Medical Center and Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Dr. Ariel L. Barkan, University of Michigan Medical Center, 1500 East Medical Center Drive, 3920 Taubman Center, Box 0354, Ann Arbor, Michigan 48109. E-mail: abarkan{at}umich.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
GH secretory profiles in humans are pulsatile and exhibit nocturnal elevation during the early hours of sleep. Fasting augments GH output and rhythmicity. Ghrelin was suggested to exhibit nocturnal increases and to rise in response to nutritional deprivation. We examined whether ghrelin may be an underlying mechanism of GH rhythmicity and response to fasting. We studied nine young healthy subjects during normal feeding and after 2 d of complete fasting. Plasma GH was measured every 10 min, and plasma total and active ghrelins were measured every 20 min. Fasting augmented mean daily plasma GH (1.47 ± 0.25 vs. 3.30 ± 0.6 µg/liter; P = 0.012). Neither mean daily total ghrelin (4.19 ± 0.64 vs. 4.35 ± 0.74 µg/liter; P = 0.75) nor mean daily active ghrelin (0.13 ± 0.02 vs. 0.13 ± 0.02 µg/liter; P = 0.34) changed as a result of fasting. All subjects exhibited nocturnal augmentation of GH secretion; there were no corresponding nocturnal increases in either total or active ghrelin concentrations. Similarly, cross-correlation analysis failed to find any relation between GH and ghrelin pulses. We conclude that ghrelin is unlikely to be of importance in the generation of rhythmic or nutritionally mediated GH secretion.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GHRELIN, A 28-AMINO-acid-acylated peptide, was suggested to be a powerful endogenous regulator of GH release in humans, with biological actions distinct from those of GHRH. Ghrelin has strong dose-related GH-releasing activity (1) mediated by the activation of GH secretagogue (GHS) receptor type 1a (2). Ghrelin and synthetic GHS are synergistic with GHRH in stimulating pituitary GH secretion in humans (3) and require GHRH for their full action, as indicated by the reduction of their stimulatory effect on GH secretion after pretreatment with the GHRH receptor antagonist (4).

Ghrelin is predominantly produced in and released from the stomach (5), but it is expressed in a variety of other tissues, including pituitary, placenta, lymphocytes, testes, lungs, kidney, pancreas, and hypothalamus (6, 7). Nutritional factors have been reported to affect ghrelin secretion, with its circulating levels being increased after fasting and decreased after feeding (8, 9, 10). Based on this information, ghrelin was proposed as an important stimulus for hunger and meal initiation behavior and as an endogenous regulator of energy homeostasis (8).

In humans, ghrelin secretion is reported to be sexually dimorphic, with women in the late follicular stage having higher levels than men (11), and recent studies concluded that the sexual dimorphism in ghrelin levels is largely mediated by central adiposity (12).

The role of endogenous ghrelin in the complex neuroendocrine mechanisms regulating GH secretion is unknown. GH secretion is pulsatile and characterized by periodic secretory bursts occurring on the background of long daytime periods of secretory quiescence. There is a characteristic nocturnal augmentation of GH secretion superimposed on the underlying pulsatile pattern, resulting from increased amplitude and higher frequency of GH pulses (13). Fasting augments daily GH output and rhythmicity (14). The genesis of all of these salient features of GH secretion is thought to result from interplay of hypothalamic GHRH and somatostatin (SRIF). However, certain physiological paradigms hint at the existence of an additional regulator of GH pulsatility. For example, GH pulsatility persists in the face of a continuous supraphysiological milieu of the SRIF agonist, octreotide (15), and is augmented by continuous GHRH infusion (16, 17). The nocturnal GH peak is powerfully attenuated by a specific GHRH receptor antagonist (18), thus demonstrating its GHRH dependence. However, nocturnal augmentation persists during pulsatile administration of GHRH boluses (19) and even during continuous GHRH infusion (17). This suggests that altered pituitary sensitivity to GHRH may play a role in spontaneous GH secretion, perhaps through a nocturnal fall in SRIF secretion. However, the nocturnal GH peak is not abolished by continuous infusion of the superactive SRIF analog, octreotide (15).

These data have suggested the existence of an additional, non-GHRH, non-SRIF regulator of GH secretion. To account for the above inconsistencies, this factor should be released periodically, potentiate the pituitary sensitivity to GHRH (and/or augment GHRH secretion), antagonize the GH inhibitory action of SRIF, and increase during fasting. Also, this factor might be activated during the early evening hours. Ghrelin seems to possess all of the above characteristics (20), thus fulfilling the requirements for the third regulator of pituitary GH pulsatility. Specifically, it potentiates GHRH action, may by itself cause hypothalamic GHRH release, is a partial functional SRIF antagonist (21), is nutritionally regulated (22), and was even suggested to increase early in the evening (8). Therefore, we hypothesized that ghrelin might play a role in GH pulse generation and in the nocturnal augmentation of GH secretion. We compared daily profiles of plasma GH, total ghrelin, and active (acylated) ghrelin during fed and fasting conditions to establish whether ghrelin levels increase during short-term fasting and whether acute changes in ghrelin concentrations might correlate with GH pulsatility and diurnal rhythmicity.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The study was approved by the institutional review board of University of Michigan Medical School and the operating subcommittee of the General Clinical Research Center. All subjects signed an informed consent document before participation in the study. Nine young (age, 20.7 ± 1.4 yr) subjects (body mass index, 28.4 ± 2.2 kg/m2) were studied during normal feeding and after 2 d of complete fasting. There were five men and four women. All subjects were healthy, did not take any medications, and had normal physical examinations and screening biochemical and hematological tests. All were hospitalized at the General Clinical Research Center for 3 d. During the first day they were fed a standardized weight maintenance hospital diet (meals served at 0800, 1200, and 1700 h), then fasted for a period of 63 h. They were allowed to sleep (lights off) between 2300–0700 h. During the day the lights were on, and sleeping and snacking was not permitted. Blood sampling was performed through an indwelling venous cannula every 10 min for 24 h during the first and third days of the protocol between 0800 and 0800 h, i.e. between 39 and 63 h of fasting. The indwelling venous cannulas were kept patent by slow infusion of normal saline.

Assays

Plasma GH was measured on both occasions every 10 min by immunochemiluminescent assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) with a sensitivity 0.01 µg/liter. Plasma total and active ghrelin concentrations were measured every 20 min by RIA (Linco Research, Inc., St. Charles, MO) with sensitivities of 0.1 and 0.01 µg/liter, respectively. Blood samples for total and acylated ghrelin were collected in EDTA tubes and kept on ice. Plasma was separated within 30 min of the blood draw and acidified with 1 N HCl, and the samples were stored at –20 C until assaying. Both total and active ghrelin assays were performed on the same day to minimize the number of thawings. All samples were assayed in duplicate. Both intra- and interassay variabilities were less than 10%.

Statistical analysis

Mean 24-h values were compared with paired Student’s t tests, using log-transformed values. Mean hormone concentrations in 24 1-h blocks were also calculated. These data were analyzed by ANOVA with repeat measures to assess the diurnal rhythmicity of the hormones. The concordance between GH and total and active ghrelin was studied by cross-correlation analysis using lag periods between –60 and 60 min in 20-min segments. Data are shown as the mean ± SEM, and P < 0.05 was regarded as statistically significant.

Pulse analysis was performed for GH, total ghrelin, and active ghrelin 24-h profiles using the Cluster algorithm as described previously (23). Trough values were calculated as the mean of the lowest 5% of hormone concentrations in each particular series.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Initially, mean concentrations of GH, total ghrelin, and active ghrelin were compared between men and women separately during both fed and fasting states. No statistical difference in plasma GH between men and women was found during fed (1.5 ± 0.32 and 1.44 ± 0.45 µg/liter; P = 0.91) and fasting (3.92 ± 0.95 and 2.52 ± 0.53 µg/liter; P = 0.28) states. There was no significant difference between men and women in basal (fed) mean daily total ghrelin (3.3 ± 0.59 and 5.31 ± 1.05 µg/liter; P = 0.12) or active ghrelin (0.11 ± 0.01 and 0.15 ± 0.04 µg/liter; P = 0.37) or in fasting mean daily total ghrelin (3.56 ± 0.78 and 5.35 ± 1.32 µg/liter; P = 0.26) and active ghrelin (0.14 ± 0.04 and 0.11 ± 0.03 µg/liter; P = 0.45). Thus, the data for both sexes were combined into a single group.

Figure 1Go shows a full set of hormonal data obtained from a representative subject (a 21-yr-old male).



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  		FIG. 1. Actual plasma GH, ghrelin, and active ghrelin concentrations during the fed (left) and fasting (right) states in a representative subject (a 21-yr-old man).

 
Figure 2Go, upper panel, shows the composite picture of GH profiles in the entire group during normal feeding and after 2 d of fasting. Fasting augmented mean daily plasma GH (1.47 ± 0.25 to 3.30 ± 0.6 µg/liter; P = 0.012). All subjects exhibited nocturnal augmentation of GH secretion, with a peak between 2300 and 0200 h (P = 0.01 during both fed and fasting states). The absolute nocturnal GH maxima were 7.9 ± 1.8 and 11.7 ± 2.3 µg/liter, respectively (P = 0.11).



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  		FIG. 2. Hormone profiles in nine subjects during normal feeding (•) and after 2 d of fasting ({circ}).

 
Fig. 2Go, middle and lower panels, shows total ghrelin and active ghrelin profiles, respectively, in the entire group during normal feeding and after 2 d of fasting. Neither mean daily total ghrelin (4.19 ± 0.64 vs. 4.35 ± 0.74 µg/liter; P = 0.75) nor mean daily active ghrelin (0.13 ± 0.02 vs. 0.13 ± 0.02 µg/liter; P = 0.34) changed as a result of fasting. The ratio of acylated to desacylated ghrelin observed in this study (~3%) was virtually identical with that found in rats (~1.8%) and humans (~3.2%) (24, 25). There were no nocturnal increases in total or active ghrelin levels (P > 0.3 for all) to correspond with nocturnal GH augmentation.

Fasting augmented the mean GH pulse frequency (9.11 ± 0.56 to 11.56 ± 0.6 pulses/24 h; P = 0.01) and the mean trough GH (0.07 ± 0.02 to 0.44 ± 0.14 µg/liter; P = 0.03), but did not alter the mean pulse amplitude (3.1 ± 0.32 to 3.6 ± 0.67 µg/liter; P = 0.26). Neither mean total ghrelin pulse frequency (8.22 ± 0.56 vs. 9.22 ± 0.52 pulses/24 h; P = 0.13) nor mean trough total ghrelin (2.14 ± 0.52 vs. 2.37 ± 0.54 µg/liter; P = 0.15) changed with fasting. Active ghrelin pulse frequency decreased with fasting (8.22 ± 0.32 vs. 6.67 ± 0.55 pulses/24 h; P = 0.02), but mean trough active ghrelin did not change (0.02 ± 0.003 vs. 0.03 ± 0.003 µg/liter; P = 0.3).

Cross-correlation analysis (Fig. 3Go) did not reveal any evidence of concordance between GH and total ghrelin (r2 = 0.015–0.05; P = 0.27–0.68) or GH and active ghrelin pulses (r2 = 0.03 to 0.11; P = 0.07–0.5) either before or after fasting, with lag periods of 20 min between the two ranging from –60 to 60 min.



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  		FIG. 3. Cross-correlation analysis of GH and total/active ghrelin during normal feeding and after 2 d of total fasting. Data from individual subjects are shown ({circ}). The mean ± SE data for the entire set of subjects are shown (•). GH and ghrelin concentrations did not correlate at any lag (20 min) period.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study we attempted to ascertain the role of ghrelin as a potential regulator of GH pulsatility, nocturnal GH augmentation, and activation of the somatotropic axis by fasting. To this end, we measured plasma levels of GH and total and active (octanoylated) ghrelin in normal men and women during fed and fasting states.

Some studies (11) have suggested the existence of sexual dimorphism of ghrelin secretion, with total ghrelin being higher in women. In this study there was also an impression that total ghrelin levels were higher in women, but the differences were not statistically significant, probably as a result of the limited number of subjects in each group. However, because the points of interest in this study were common to both sexes (the existence of GH pulses, nocturnal GH augmentation, and amplification of GH secretion by fasting), we were able to study all individuals as a single group, with each one serving as his/her own control. Some studies have claimed the existence of a nocturnal ghrelin rise (8), but this assertion was based on visual impression only and was not supported by appropriate statistical analysis. Moreover, the above studies did not measure the active form of ghrelin. In the present study, as well as in a recent study by Koutkia et al. (26), the GH secretory pattern exhibited, as expected, strong nocturnal augmentation. However, this was not accompanied by parallel changes in ghrelin concentrations, indicating that nocturnal GH release is not mediated by a concomitant increase in ghrelin secretion.

GH secretion is amplified by fasting (27). Ghrelin concentrations were reported to decline postprandially (10) and to be grossly elevated in patients with anorexia nervosa (28). Based on this information, it was assumed that ghrelin secretion is augmented by fasting, perhaps as a response to gastric lack of nutrients (8) and, in turn, serves as an orexigenic stimulus (29). Our data do not confirm either of these postulates. Neither total nor active forms of ghrelin increased to any appreciable degree even on the second day of fasting, when the subjects exhibited a marked sense of hunger, and nutrient contact with the gastric mucosa was most certainly absent. Thus, our data do not support the idea that the fasting-induced amplification of GH secretion can be explained by ghrelin dynamics. Recent data reported by Liu et al. (30), who used different ghrelin assays, support our finding of the lack of ghrelin augmentation by fasting. Perhaps longer periods of nutrient deprivation may be needed to amplify ghrelin secretion. Whether high ghrelin levels in patients with anorexia (28) reflect a profound catabolic state or are an independent feature of this disease is unknown. However, our data clearly indicate that the fasting-induced GH amplification is not a ghrelin-mediated phenomenon. In this study we did not control for the precise timing of meal initiation or for a specific nutrient composition of meals. Both of these factors appear to be crucial for determination of the postprandial ghrelin dynamics (31, 32, 33, 34), and this likely explains our inability to detect postprandial ghrelin declines.

Third, we investigated whether the timing of spontaneous GH pulses may involve the participation of circulating ghrelin. To this end we performed cross-correlation analysis of GH/ghrelin and GH/active ghrelin. We could not demonstrate any concordance between GH and ghrelin pulses, even when a lag period as long as 60 min was modeled in both directions (i.e. ghrelin preceding GH, or GH preceding ghrelin). Recently, Koutkia et al. (26) suggested a relatedness between ghrelin and GH pulsatility based on the cross-approximate entropy analysis. Additional studies may be needed to resolve this problem.

Thus, overall, we failed to find any obvious involvement of systemic ghrelin in the genesis of the three most prominent characteristics of GH release: pulsatility, nocturnal augmentation, and amplification by fasting. It is still possible that ghrelin may play a permissive role in the regulation of GH secretion in humans. Administration of ghrelin agonists, for example, increases GH pulse amplitude (35), probably by amplifying the effect of endogenous GHRH pulses (36). If this is the case, patients after total gastrectomy would be expected to have attenuated GH output with low GH pulse amplitude. We are unaware of any data from such a model. Whether lower ghrelin levels in obesity may explain the attenuated GH secretion is likewise unknown. In contrast, ghrelin/GHS antagonist did not alter parameters of GH pulsatility in male rats, and both ghrelin and ghrelin receptor knockout mice exhibited no appreciable changes in growth (37, 38). Conversely, no increase in GH and IGF-I concentrations was seen in two patients with malignant ghrelinomas and plasma ghrelin concentrations orders of magnitude above the upper normal range (39, 40).

Additional studies may reveal certain aspects of GH regulation that are governed by ghrelin. However, our data do not provide support for a theory that circulating ghrelin is an important regulator of endogenous GH secretion in humans.


   Acknowledgments
 
We thank all the participants in this study for their cooperation, the staff of the University of Michigan General Clinical Research Center for their excellent care of the subjects, and Dr. Morton Brown and Wen Ye for assistance with statistical analysis.


   Footnotes
 
This work was supported by a Veterans Affairs Medical Research Service Merit Review Grant (to A.L.B.) and Grant M0-1-RR00042 (to University of Michigan General Clinical Research Center).

First Published Online February 15, 2005

Abbreviations: GHS, GH secretagogue; SRIF, somatostatin.

Received September 9, 2004.

Accepted February 7, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals