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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 11 5478-5483
Copyright © 2003 by The Endocrine Society

Neuroendocrine and Metabolic Effects of Acute Ghrelin Administration in Human Obesity

F. Tassone, F. Broglio, S. Destefanis, S. Rovere, A. Benso, C. Gottero, F. Prodam, R. Rossetto, C. Gauna, A. J. van der Lely, E. Ghigo and M. Maccario

Division of Endocrinology and Metabolism (F.T., S.D., S.R., A.B., C.G., F.P., R.R., E.G., M.M.), Department of Internal Medicine, University of Turin, 10126 Turin, Italy; and Division of Endocrinology and Metabolism (F.B., C.G., A.J.v.d.L.), Department of Internal Medicine, Erasmus University, 3015 Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: E. Ghigo, M.D., Department of Internal Medicine, Division of Endocrinology. Corso Dogliotti 14, 10126 Torino, Italy. E-mail: ezio.ghigo{at}unito.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Ghrelin stimulates appetite and plays a role in the neuroendocrine response to energy balance variations. Ghrelin levels are inversely associated with body mass index (BMI), increased by fasting and decreased by food intake, glucose load, insulin, and somatostatin. Ghrelin levels are reduced in obesity, a condition of hyperinsulinism, reduced GH secretion, and hypothalamus-pituitary-adrenal axis hyperactivity. We studied the endocrine and metabolic response to acute ghrelin administration (1.0 µg/kg iv) in nine obese women [OB; BMI (mean ± SD) 36.3 ± 2.3 kg/m2] and seven normal women (NW; BMI 20.3 ± 1.7 kg/m2). Basal ghrelin levels in NW were higher than in OB (P < 0.05). In NW, ghrelin increased (P < 0.05) GH, prolactin (PRL), ACTH, cortisol, and glucose levels but did not modify insulin. In OB, ghrelin increased (P < 0.01) GH, PRL, ACTH, and cortisol levels. The GH response to ghrelin in OB was 55% lower (P < 0.02) than in NW, whereas the PRL, ACTH, and cortisol responses were similar. In OB, ghrelin increased glucose and reduced insulin (P < 0.05). Thus, obesity shows remarkable reduction of the somatotroph responsiveness to ghrelin, suggesting that ghrelin hyposecretion unlikely explains the impairment of somatotroph function in obesity. On the other hand, in obesity ghrelin shows preserved influence on PRL, ACTH, and insulin secretion as well as in glucose levels.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GHRELIN IS A 28-amino-acid peptide produced predominantly by the stomach, although it is expressed also by other tissues including the bowel, pancreas, kidneys, lung, placenta, gonads, pituitary, and hypothalamus (1, 2, 3). In its acylated form, ghrelin displays strong GH-releasing activity mediated by the activation of the GH secretagogue (GHS) receptor (GHS-R) type 1a; GHS-Rs are expressed in the hypothalamus-pituitary unit but also in other central and peripheral tissues (2, 3, 4, 5, 6, 7, 8, 9).

Besides stimulating GH secretion, ghrelin has other endocrine and nonendocrine actions including stimulation of lactotroph and corticotroph secretion, inhibition of gonadal axis, orexigenic effect coupled with control of energy expenditure, control of gastric motility and acid secretion, influence on both endocrine and exocrine pancreatic function and on glucose metabolism, cardiovascular actions, influence on behavior and sleep, modulation of cell proliferation, and apoptosis (2, 10, 11).

Circulating ghrelin levels are mainly represented by the unacylated form (despite the endocrine actions are exerted by the acylated form only) and mostly reflect gastric secretion; in fact, they are reduced by 70% after gastrectomy and also after gastric bypass in humans (10, 12, 13). Ghrelin secretion occurs in pulsatile manner without strict correlation with GH levels but with association to food intake episodes and sleep cycles in rats (14). In humans, ghrelin secretion undergoes remarkable variations throughout the day and, like in animals, ghrelin peaks anticipate food intake, suggesting that the latter is triggered by ghrelin discharge (10, 15, 16), although these findings have not been confirmed by others (17).

Circulating ghrelin levels are increased by fasting and energy restriction and decreased by food intake (10, 12, 13, 15, 18). Moreover, ghrelin secretion shows negative correlation with body mass index (BMI). In fact, circulating ghrelin levels are increased in anorexia and cachexia, reduced in obesity with or without diabetes type 2, and restored by weight recovery (15, 19, 20, 21, 22). Interestingly, these changes are opposite to those of leptin, and it has been suggested that both ghrelin and leptin signal the metabolic balance and manage the neuroendocrine and metabolic response to starvation (2, 10, 23).

Ghrelin and insulin secretion are negatively associated, and an inhibitory influence of insulin on ghrelin secretion has been shown both in animals and humans (11, 15, 24, 25, 26, 27, 28, 29). For instance, both euglycemic and hypoglycemic hyperinsulinemic clamps reduce circulating ghrelin levels in humans (24, 30).

With regard to nutrients, glucose has inhibitory influence on ghrelin secretion as indicated by the clear decrease in circulating ghrelin levels after either oral or iv glucose load (19, 31, 32). On the other hand, iv free fatty acid as well as arginine load does not affect circulating ghrelin levels in humans (Ref. 24 and our unpublished results).

Besides hyperinsulinism, obesity is characterized by several endocrine abnormalities including reduced GH secretion and hyperactivity of the hypothalamus-pituitary-adrenal axis (HPA) (33, 34, 35, 36, 37). Both spontaneous and stimulated GH secretion is reduced in obese patients mostly reflecting true impairment of the GH production rate (33). The somatotroph responsiveness to the most potent provocative stimuli, including GHS, is impaired in obesity often to an extent as marked as in hypopituitary patients with GH deficiency (35, 36). The impairment of somatotroph function in obesity could reflect neuroendocrine dysfunctions, but recent evidence more strongly supports the hypothesis that abnormalities in metabolic factors and peripheral hormones play the major role (35, 36).

HPA hyperactivity in obese patients with visceral adiposity does not lead to an increase in cortisol production rate but is reflected by altered ACTH pulsatile secretory pattern and clear ACTH hyperresponsiveness to provocative stimuli such as insulin-induced hypoglycemia, CRH, and arginine vasopressin (AVP) (37). The impaired sensitivity to the negative feedback action of glucocorticoids in obesity could explain the corticotroph dysregulation, which, in turn, might also reflect other neuroendocrine and/or metabolic alterations such as hyperinsulinism and high levels of free fatty acids (34, 37).

It has been hypothesized that ghrelin could play a major role in the endocrine abnormalities that are commonly present in obesity (2, 23). Thus, the aim of this study was to define the effects of ghrelin on somatotroph, lactotroph, and corticotroph secretion as well as on insulin and glucose levels in women with visceral obesity. The results in the obese patients were compared with those from a group of normal young women. In both groups morning ghrelin and IGF-I levels after overnight fasting have also been measured.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Nine women with visceral obesity [OB; age (mean ± SD) 33.0 ± 3.7 yr; BMI 36.3 ± 2.3 kg/m2; waist circumference 108.2 ± 7.0 cm] and seven normal young women (NW; age 30.6 ± 8.0 yr; BMI 20.3 ± 1.7 kg/m2, waist circumference 70.1 ± 4.8 cm) were studied in their early follicular phase. None of the subjects had been under any medication in the last 3 months before entering the study. All subjects gave their written informed consent to participate in the study, which had been approved by an independent ethical committee.

All subjects underwent the following two testing sessions: 1) ghrelin (1.0 µg/kg as iv bolus at time 0 min); and 2) saline (3 ml as iv bolus at time 0 min).

After an overnight fasting, tests began in the morning at 0830–0900 h, 30 min after an indwelling catheter had been placed into an antecubital vein of the forearm kept patent by the slow infusion of isotonic saline.

Blood samples were taken every 15 min from time -15 up to +90 min. GH, prolactin (PRL), ACTH, cortisol, insulin, and glucose levels were assayed at each time point. Basal morning ghrelin and IGF-I levels were also measured.

Serum GH levels (microgram per liter) were measured in duplicate by immunoradiometric assay (IRMA) (human GH-CTK IRMA, SORIN Biomedica, Saluggia, Italy). The sensitivity of the assay was 0.15 µg/liter. The inter- and intraassay coefficients of variation were 2.9–4.5% and 2.4–4.0%, respectively.

Serum PRL levels (microgram per liter) were measured in duplicate by IRMA (PRL-CTK, SORIN Biomedica). The sensitivity of the assay was 0.5 µg/liter. The inter- and intraassay coefficients of variation ranged from 3.9–6.8% and from 3.3–7.5%, respectively.

Plasma ACTH levels (picograms per milliliter, 1 pg/ml = 0.2202 pmol/liter) were measured in duplicate by IRMA (Allegro HS-ACTH, Nichols Institute Diagnostic, San Juan Capistrano, CA). The sensitivity of the assay was 1 pg/ml. The inter- and intraassay variation coefficients ranged between 2.4 and 8.9% and between 3.9 and 9.9%, respectively.

Serum cortisol levels (microgram per liter; 1 µg/liter = 2.759 nmol/liter) were measured in duplicate by RIA (CORT-CTK 125, IRMA, SORIN Biomedica). The sensitivity of the assay was 4.0 µg/liter. The inter- and intraassay coefficients of variation ranged from 6.6–7.5% and from 3.8–6.6%, respectively.

Serum insulin levels (mU/liter; 1 mU/liter = 7.175 pmol/liter) were measured in duplicate by IRMA (INSIK-5, SORIN Biomedica). The sensitivity of the assay was 2.5 ± 0.3 mU/liter. The inter- and intraassay coefficients of variation were 6.2–10.8% and 5.5–10.6%, respectively.

Plasma glucose levels (milligrams per deciliter; 1 mg/dl = 0.05551 mmol/liter) were measured by glucooxidase colorimetric method (GLUCOFIX, by Menarini Diagnostici, Florence, Italy).

Serum IGF-I levels (microgram/liter) were assayed by IRMA (Nichols Institute Diagnostics) after acid-ethanol extraction to avoid interference by binding proteins. The sensitivity of the method is 0.1 µg/liter. The inter- and intraassay coefficients of variation are 8.8–10.8% and 5.0–9.5%, respectively.

Plasma total ghrelin levels (picogram per milliliter) were measured after extraction in reverse phase C18 columns (Strata C18-E, Phenomenex, Torrance, CA) by radioimmunometric assay (Phoenix Pharmaceuticals, Inc., Belmont, CA) using 125I-labeled bioactive ghrelin as a tracer and a rabbit polyclonal antibody vs. octanoylated and des-octanoylated human ghrelin. Plasma samples have been acidified with an equal amount of 1% trifluoroacetic acid in H2O. Then it was centrifuged at 8000 x g for 20 min at 4 C, and the supernatant was kept. A SEP-COLUMN containing 200 mg of C18 was equilibrated by washing with 60% acetonitrile in 1% trifluoroacetic acid followed by 1% trifluoroacetic acid in H2O. The acidified plasma solution was loaded onto the pretreated C18 SEP-COLUMN. The column was then washed with 1% trifluoroacetic acid in H2O and the wash discarded. The peptide was eluted slowly with 60% acetonitrile in 1% trifluoroacetic acid and the eluant collected in a polypropylene tube. The eluent was then evaporated to dryness in a centrifugal concentrator and then reconstituted to the original value. Sensitivity was 30 pg/tube. Based on our data, the intraassay coefficient of variation range was 0.3–10.7%.

All samples from an individual subject were analyzed together.

GH, PRL, ACTH cortisol, insulin, glucose, ghrelin, and IGF-I levels are expressed as absolute or {delta} areas under curves (AUC) calculated by trapezoidal integration.

The statistical analysis was carried out using a nonparametric ANOVA (Friedman test) and then Wilcoxon matched pairs test or Mann-Whitney U test as appropriate.

Results are expressed as mean ± SD.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Basal morning ghrelin levels in OB (119.5 ± 216.5 pg/ml) were lower (P < 0.05) than NW (243.5 ± 202.11 pg/ml). Also, basal GH levels were lower (P < 0.05) in OB than NW (0.7 ± 0.6 vs. 5.6 ± 4.5 µg/liter), but IGF I levels in OB and NW (220.4 ± 402.6 vs. 250.3 ± 453.6 µg/liter) were similar. Basal glucose and insulin levels in OB were higher (P < 0.05) than in NW (82.8 ± 10.2 vs. 67.9 ± 11.1 mg/dl and 33.1 ± 6.9 vs. 13.2 ± 5.6 mU/liter). ACTH and cortisol levels at baseline were similar in both groups.

After placebo no significant variation was recorded in terms of GH, PRL, insulin, and glucose levels. Significant (P < 0.01) spontaneous reduction of ACTH and cortisol levels was detected (Table 1Go).


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  		TABLE 1. Mean (±SD) GH, PRL, ACTH, and cortisol AUC levels after saline or ghrelin (1.0 µg/kg iv) administration in NW and in obese patients

 
In NW ghrelin administration induced marked increase (P < 0.001) of circulating GH levels (Table 1Go, Fig. 1Go). Ghrelin administration also increased (P < 0.01) PRL, ACTH, and cortisol levels (Table 1Go).



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  		FIG. 1. Mean (±SD) GH response to ghrelin administration (1.0 µg/kg iv as a bolus at 0 min) in NW and obese patients.

 
After ghrelin administration, an increase (P < 0.05) in glucose levels was also recorded ({Delta}AUC: 404.9 ± 559.5 mg·min/dl), whereas insulin levels did not show any significant change ({Delta}AUC: -47.2 ± 154.1 mU·min/liter) (Fig. 2Go).



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  		FIG. 2. Mean (±SD) insulin and glucose levels after saline or ghrelin (1.0 µg/kg iv as a bolus) administration in NW and obese patients.

 
In OB, as in NW, ghrelin induced increase (P < 0.01) of GH, PRL, ACTH, and cortisol levels (Table 1Go). However, the ghrelin-induced GH release in OB was clearly lower (P < 0.02; 55% less) than in NW (Fig. 1Go). On the other hand, the PRL, ACTH, and cortisol responses to ghrelin in OB were similar to those in NW (Table 1Go).

As in NW, in OB ghrelin administration increased (P < 0.05) glucose levels ({Delta}AUC: 330.4 ± 222.1 mg·min/dl) (Fig. 2Go). In OB, ghrelin also induced significant (P < 0.05) reduction of insulin levels ({Delta}AUC: -288.2 ± 424.2 mU·min/liter) (Fig. 2Go).

Side effects

After ghrelin administration, four NW and five OB showed a transient facial flushing, whereas five NW and six OB referred to be hungry at the end of the testing session.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of the present study demonstrate that obesity, a condition of ghrelin and GH hyposecretion, shows reduced somatotroph responsiveness to the administration of exogenous ghrelin. This GH hyporesponse is coupled with normal PRL and ACTH responses. Moreover, our findings also show that in obesity ghrelin enhances plasma glucose levels and induces transient decrease in insulin levels.

Reduced somatotroph secretion in obesity reflects true impairment of GH production rate and has been demonstrated either in term of spontaneous secretion as well as in terms of somatotroph response to provocative stimuli (35, 36). In agreement with evidence that the GH releasable pool in obesity is not exhausted (38, 39, 40), the somatotroph secretion in obesity has been reported restored by long-term diet and marked weight loss but not by short-term fasting (35, 36). It has been hypothesized that the impaired GH secretion in obesity could reflect neuroendocrine abnormalities, but a major role for abnormalities in peripheral hormones and metabolic factors has been more recently emphasized (35, 36).

Synthetic GHS mimics the actions of ghrelin that activates specific central and peripheral GHS-Rs and displays strong GH-releasing activity reflecting pituitary and mainly hypothalamic actions probably by triggering GHRH-secreting neurons and functional antagonism of somatostatin activity (2, 10, 41, 42). Among several other actions, ghrelin also stimulates lactotroph and corticotroph secretion; has orexigenic effect; and influences energy balance, insulin secretion, glucose, and lipid metabolism (2, 10, 11). As in obesity, ghrelin levels have been described to be reduced and ghrelin secretion to be peculiarly refractory to the inhibitory effect of food intake (Refs. 13 , 19 , 21, 22, 23 , 43 , and 44 , and present results); it has been hypothesized that the impaired ghrelin secretion and/or action could have a role in the neuroendocrine and metabolic alterations in obesity (23).

In particular, impaired ghrelin secretion has been proposed to explain the impairment of the somatotroph function in obesity. Indeed, after ghrelin administration we found an increase in circulating GH levels in agreement with similar results obtained after administration of synthetic GHS (38, 39, 40). This GH response agrees with the assumption that the pituitary GH releasable pool is not exhausted in obesity (36, 38, 39, 40), but it has to be emphasized that the GH response to ghrelin in obese patients is clearly lower than that in normal controls (more than 50% less). Although a dose response study would better describe the sensitivity to the GH-releasing effect of ghrelin in obesity, our present findings showing the low GH response to a nearly maximal dose of ghrelin in obese patients do not support the hypothesis that ghrelin hyposecretion is fully responsible for the impairment of GH secretion in obesity. This would agree with some studies (17, 45, 46) questioning the strict functional relationship between ghrelin and GH secretion that, in turn, is supported by other studies (47, 48, 49, 50, 51).

Because it is widely accepted that ghrelin and GHRH truly synergize (9, 52), the concomitant hypoactivity of the GHRH-secreting neurons in obesity would well contribute to the reduced GH response to exogenous ghrelin in obese patients (35, 36). This hypothesis has to be clarified by studying the GH response to combined administration of ghrelin and GHRH in obesity.

The reduced GH response to ghrelin unlikely reflects alterations in the hypothalamic somatostatinergic activity that has never been definitely demonstrated in obesity (36, 53).

On the other hand, a peculiar hypersensitivity of the GH-releasing effect of ghrelin and GHS to the negative feedback effect of IGF-I (54, 55) would explain the blunted GH response to ghrelin in obesity. In fact, in obesity, despite clear reduction in GH secretion, total IGF-I levels are normal or slightly reduced (36 and present results), and free IGF-I levels have even been found increased (36). This picture of IGF-I levels despite reduced GH secretion in obesity is also confirmed by our present study and would reflect the sensitizing effect of insulin on IGF-I synthesis and secretion (36). Insulin hypersecretion as well as chronically elevated levels of free fatty acids in obesity could in turn per se play a role in blunting the GH response to exogenous ghrelin as well as to all known provocative stimuli (36).

Besides insulin-induced hypoglycemia and glucagon, natural (i.e. ghrelin) and synthetic GHS represents one of the few stimuli allowing concomitant evaluation of somatotroph and corticotroph function (56). In fact, ghrelin strongly stimulates GH but also exerts significant stimulatory effect on ACTH and PRL levels; it has been demonstrated that the stimulatory action of ghrelin on corticotroph and lactotroph secretion is constitutive and not simply not specific (2, 5).

Our study shows that in obese patients the blunted GH response to ghrelin is coupled with an ACTH and cortisol responsiveness similar to that in normal subjects. Indeed, the ACTH response to ghrelin showed a trend toward enhancement with respect to normal subjects. These findings agree with previous studies in which the effects of synthetic GHS on HPA activity in obesity have been evaluated (38). Moreover, ACTH hyperresponsiveness to CRH and/or AVP have been demonstrated in obesity (37), and both CRH and AVP as well as neuropeptide Y, at least partially, mediate the ACTH-releasing activity of ghrelin and synthetic GHS (2). In all, these findings agree with the assumption that obesity is accompanied by concomitant alterations in the control of somatotroph and corticotroph function (2, 35, 37).

Alterations of PRL secretion in obesity have been reported (57), but we did not find any change in the PRL response to ghrelin, in agreement with what had been observed after administration of synthetic GHS (38).

Our study also shows that in obese women the acute administration of ghrelin is followed by increase in plasma glucose levels coupled with transient reduction in insulin secretion.

Ghrelin administration has been reported able to modulate insulin secretion both in humans and rats (11, 58, 59, 60, 61). In humans, this effect has been demonstrated in both sexes by some but not by other authors (62, 63). In our present study, the administration of exogenous ghrelin in normal women was not followed by significant change in insulin levels that, however, were significantly inhibited in obese women. Because ghrelin and GHS-Rs are expressed within the endocrine pancreas, it is reasonable to hypothesize that ghrelin would exert endocrine and/or autocrine/paracrine actions at the levels of the endocrine pancreas (59, 64, 65).

The increase in glucose levels that follows the administration of exogenous ghrelin is, however, unlikely to be reflecting the slight reduction in insulin levels, nor variations in glucagon levels that, in fact, have been reported to be unaffected by acute ghrelin administration in humans (58, 62).

Therefore, theoretically the hyperglycemic effect of ghrelin might be explained by an increase of catecholamine release or of circulating somatostatin levels that have been both described in humans after acute ghrelin administration (63, 66). However, other unknown metabolic actions of ghrelin cannot be definitely ruled out.

In conclusion, this study demonstrates that obesity, a condition of ghrelin and GH hyposecretion, shows reduced somatotroph responsiveness to ghrelin administration. The administration of this nearly maximal dose of exogenous ghrelin in obese patients also elicits a normal PRL and ACTH response as well as normal impact on insulin secretion and glucose levels. A dose-range study addressing the endocrine response to ghrelin would definitely clarify the hypothesis that the sensitivity to ghrelin in obese patients is impaired.


   Acknowledgments
 
The authors thank E. Arvat, L. Gianotti, and E. Massimetti for their collaboration. The skillful technical assistance of Dr. A. Bertagna, Mrs. A. Barberis, and Mrs. M. Talliano is also acknowledged.


   Footnotes
 
This work was supported by Ministero dell’Università e della Ricerca Scientifica e Tecnologica, University of Turin, Eureka (Peptido project 1923), Fondazione per lo Studio delle Malattie Endocrino Metaboliche (FSMEM), and Europeptides.

Abbreviations: AUC, Area under curve; AVP, arginine vasopressin; BMI, body mass index; GHS, GH secretagogue; GHS-R, GHS receptor; HPA, hypothalamus-pituitary-adrenal axis; IRMA, immunoradiometric assay; NW, normal women; OB, women with visceral obesity; PRL, prolactin.

Received April 1, 2003.

Accepted August 8, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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