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Reduction of Free Fatty Acids By Acipimox Enhances the Growth Hormone (GH) Responses to GH-Releasing Peptide 2 in Elderly Men

Departments of Clinical Endocrinology (P.S.v.D., H.P.F.K.) and Medical Physiology and Sports Medicine (H.E.C.S., W.R.d.V., M.N., E.B., E.J.W.), University Medical Center, 3508 GA Utrecht, The Netherlands; and Departments of Physiology (C.D.) and Medicine (F.F.C.), Santiago de Compostela University, 15700 Santiago de Compostela, Spain

Address correspondence and requests for reprints to: P. S. van Dam, M.D., Ph.D., Department of Clinical Endocrinology, University Medical Center L00.407, Postbus 85.500, 3508 GA Utrecht, The Netherlands. E-mail P.S.vanDam{at}digd.azu.nl

	Abstract

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GH release is increased by reducing circulating free fatty acids (FFAs). Aging is associated with decreased plasma GH concentrations. We evaluated GH releasing capacity in nine healthy elderly men after administration of GH-releasing peptide 2 (GHRP-2), with or without pretreatment with the antilipolytic drug acipimox, and compared the GHRP-2-induced GH release with the response to GHRH. The area under the curve (AUC) of the GH response after GHRP-2 alone was 4.8 times higher compared with GHRH alone (1834 ± 255 vs. 382 ± 78 µg/L·60 min, P < 0.001). Acipimox, which reduced FFAs from 607 µmol/L to 180 µmol/L, increased the GH AUC to 1087 after GHRH and to 2956 µg/L·60 min after GHRP-2 (P < 0.01). The AUC after acipimox/GHRP-2 were positively correlated with the AUC after GHRP-2 alone (r = 0.93, P < 0.01); this was also observed between acipimox/GHRH and GHRH alone (r = 0.73, P = 0.03). Significant negative correlations were observed between basal FFAs and AUC after GHRH or GHRP-2 after combining the data with and without acipimox (r = 0.58, P = 0.01 and r = 0.48, P = 0.04, respectively), and between basal FFAs and GH at t = 0 (r = -0.44, P = 0.001). Interestingly, GHRP-2 administration was followed by a significant early rise in plasma FFAs by 60% (P = 0.01), indicating an acute lipolytic effect. In conclusion, reduction of circulating FFAs strongly enhances GHRP-2-stimulated GH release in elderly men. The data indicate that the decreased GH release associated with aging can be reversed by acipimox and that the pituitary GH secretory capacity in elderly men is still sufficient.

	Introduction

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NORMAL AGING IN humans is associated with decreased activity of the GH/insulin-like growth factor I (IGF-I) axis (1, 2, 3). Circadian GH secretion in elderly subjects is characterized by decreased GH burst frequency, amplitude, and secretory burst mass (4, 5, 6); it is still unclear whether these changes are primarily a consequence of aging, or induced by the increased percentage of body fat and/or reduced insulin sensitivity, which are associated with advanced age (5, 7). Decreased activity of the GH/IGF-I axis in the elderly has been considered to be a causal factor for reduced bone and muscle mass, visceral obesity, and alterations in cognitive function (8, 9).

Explanations for the attenuated circadian GH secretion in the elderly have been various: decreased capacity of the GH-secreting cells of the anterior pituitary, increased somatostatinergic inhibitory tone, relative GHRH deficiency, or deficiency of ghrelin, a peptide of 28 amino acids that was recently found to be an endogenous ligand for the GH-releasing peptide (GHRP) receptor (3, 10). After pretreatment with L-arginine (leading to decreased somatostatinergic tone), GHRH-stimulated GH release in elderly subjects could be increased to the level of young adult subjects (11). These data suggest that enhanced somatostatinergic tone rather than defective anterior pituitary secreting capacity contributes to decreased GH release in the elderly. Similar observations have been done after the administration of the GHRP hexarelin in combination with either GHRH or L-arginine, suggesting that defective endogenous GH secretagogues such as ghrelin may also play a role in the hyposomatotropism of aging (12).

Besides this age-related decline, circadian and stimulated GH secretion are also negatively associated with obesity and fat mass. It has been demonstrated that reduction of circulating free fatty acids (FFAs) by the antilipolytic nicotinic acid analog acipimox can significantly increase GHRH-stimulated GH release both in nonobese and in obese subjects (13, 14, 15, 16, 17, 18, 19). In the elderly, Pontiroli et al. (18) demonstrated that reduction of FFAs can enhance GHRH-mediated GH release, but despite similar FFA levels after acipimox, peak GH levels were still decreased in comparison with young subjects. Although no direct evidence has been produced yet, it has been suggested that FFAs have a direct inhibitory effect on GH-secreting pituitary cells (20, 21, 22).

The age-related decline in GH secretion can be the consequence of GHRH or GHRP deficiency, resistance or deficiency of the receptors for these peptides, and/or increased somatostatinergic tone. GHRPs are known to have a stronger GH-releasing effect than GHRH (23). Therefore, in the present study, we have evaluated pituitary GH release in response to the GH secretagogue GHRP-2 after reduction of circulating FFAs by acipimox pretreatment in elderly men and compared the outcome with GH release in response to a maximal (100 µg) GHRH dose. To control for the factors that have been reported to be of importance in the responsivity of the GH/IGF-I axis, we investigated the interrelationship among the observed GH release and clinical and biochemical parameters for central obesity and insulin resistance, such as body composition, insulin to glucose ratio, and IGF-binding protein 1 (IGFBP1).

	Subjects and Methods

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Study subjects

Nine healthy elderly Caucasian men were evaluated (see Table 1 for demographic data). The inclusion criteria were: age, 65–80 yr; waist to hip ratio (WHR), 1.0; normal life style with a habitual activity level; no history of recent medical illness (including diabetes, hyperlipidemia, hypertension, and pituitary disease); and taking no medication. Written informed consent was obtained from each subject, and the protocol was approved by our institutional ethical committee.

Primarily, basal levels of FFAs, IGF-I, IGFBP-1, glucose, and insulin were assessed. Subsequently, all subjects underwent six different tests with an interval of at least one week in a random order: GHRH, acipimox-GHRH, GHRP-2, acipimox-GHRP-2, placebo, and acipimox-placebo. On all test days, the subjects came in fasting and were asked not to perform strenuous exercise in the morning. An iv catheter was placed in the forearm for blood sampling and drug administration. Blood samples were drawn 30 min before, just before, and 15, 30, 45, and 60 min after injection of GHRH or GHRP-2 (t = -30, 0, 15, 30, 45, and 60 min) for measurement of GH and FFA. Acipimox (250 mg, Nedios; Byk Pharmaceuticals, Zwanenberg, The Netherlands) was taken orally by the subjects at t = -270 and -60 min. GHRH (100 µg; GHRH Ferring; Ferring Pharmaceuticals Ltd., Hoofadorp, The Netherlands), GHRP-2 [200 µg; courtesy of Dr. C. Y. Bowers, (Tulane University, New Orleans, LA)], or placebo (2 mL saline) was injected iv at t = 0. The subjects remained fasting and supine during the tests.

Biochemical analyses

GH was measured using an immunometric technique on an Immulite Analyzer (Diagnostic Products, Los Angeles, CA). The lower limit of detection was 0.01 µg/L; and the interassay variation was 9.7, 5.6, 4.4, and 5.2% at 0.13, 0.80, 4.2, and 15.4 µg/L , respectively (n = 69). One microgram per liter equaled 2.6 mIU/L (WHO International Ref. Prep 80/505). IGF-I was measured using the IGF-I-by extraction kit (40–2100; Nichols Institute Diagnostics, San Juan Capistrano, CA). The lower limit of detection was 20 ng/mL, and the interassay variation was 8.8, 8.5, and 6.1% at 70, 200, and 450 nmol/L, respectively (n = 12). FFAs were measured by an enzymatic colorimetric method (NEFA-HA, WAKO chemicals GmbH, Germany). Plasma glucose was measured by an enzymatic glucose-oxidase method. IGFBP-1 levels were determined by RIA using a mouse monoclonal antibody raised against IGFBP-1 purified from human amniotic fluid, as described (24). Insulin was measured using an in-house competitive RIA using a polyclonal antiinsulin antibody (Caris 46), ¹²⁵I-insulin (IM 166; Amersham Pharmacia Biotech, Roosendaal, The Netherlands) as a tracer and Humuline lotnr. RS0133 (YV 2632 AMV Lilly; Lilly, Indianapolis, IN) as a standard. The lower limit of detection was 35 pmol/L, and the interassay variation was 7.9, 5.4, and 7.8% at 74, 301, and 742 pmol/L, respectively (n = 20).

Statistical analyses

GH responses to placebo, GHRH, and GHRP-2 with or without acipimox pretreatment were evaluated by calculating the area under the curve (AUC) between t = 0 and t = 60 min, as well as by the peak GH response. To compare basal GH, peak GH, and AUC after GHRH or GHRP-2 injection with or without acipimox pretreatment, a Wilcoxon matched-pairs signed-rank test was used. To evaluate which percentage of the variability of data are explained by associations between the stimulation tests with and without acipimox, we calculated correlation coefficients between the AUC for all stimulation tests separately and combined, as well for basal GH and FFA levels of all tests combined. Furthermore, the interrelationship among AUC, circulating FFA levels, and parameters of obesity or insulin resistance was calculated using these correlation coefficients. Statistical significance was accepted at P < 0.05 (two-tailed).

	Results

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GHRH- and GHRP-2-mediated GH secretion and effects of acipimox

The mean GH level increased to 8.5 µg/L after GHRH injection. In comparison with GHRH, the GH-secreting effect of GHRP-2 was over 4-fold higher, leading to a mean peak GH level of 37.8 µg/L. After pretreatment with acipimox, peak GH levels (which almost all occurred at t = 30 min) were increased by 172% after GHRH and by 63% after GHRP-2. Comparable effects of acipimox pretreatment were demonstrated if GH AUC were calculated (185% and 61%, respectively). In individual subjects, GH rose to extremely high values after combined acipimox-GHRP-2 treatment, with a maximum of 124 µg/L. Acipimox reduced FFA levels by 70% (Fig. 1 and Table 2).

View larger version (17K): [in this window] [in a new window]   Figure 1. GH responses to GHRH without () and with (•) acipimox pretreatment, as well as GH responses to GHRP-2 without () and with () acipimox pretreatment. The placebo curves are not included, but showed no response. All data are mean ± SEM.

View larger version (17K): [in this window] [in a new window]   Figure 2. Correlations between the GH response (calculated as AUC GH) after GHRH (A) or GHRP-2 (B) without and with acipimox pretreatment.

No significant correlations were observed between GH response and body weight, BMI, WHR, waist circumference, plasma leptin, IGFBP-1, IGF-I, glucose or insulin levels, and glucose to insulin ratios. Significant correlations were observed only between plasma glucose and GH peak after acipimox/GHRP-2 (r = -0.70, P 0.04), GH AUC after GHRP-2 (r = -0.67, P = 0.05), and GH AUC after acipimox/GHRP-2 (r = -0.68, P = 0.04).

FFAs and GH response

Significant correlations between basal FFAs (at t = 0) and GH responses for each individual test separately were not observed. However, if the GH and FFA levels at t = 0 of all tests (GHRH, acipimox/GHRH, GHRP-2, acipimox/GHRP-2, placebo, and acipimox/placebo) were pooled, a significant negative correlation (r = -0.44, P = 0.001) was observed, indicating that reduction of FFAs by acipimox is associated with higher basal GH levels (Fig. 3A). Furthermore, if the data of GH AUC in response to GHRH or GHRP-2 with and without acipimox were pooled, significant negative correlations were observed between FFA and GH levels (r = -0.58, P = 0.01 for GHRH, r = -0.48, P = 0.04 for GHRP-2; Fig. 3, B and C).

View larger version (15K): [in this window] [in a new window]   Figure 3. Correlation between basal FFAs (t = 0) and GH (A) at t = 0 (data from six tests with and without acipimox pretreatment pooled; see text), GH AUC after GHRH (B), and GH AUC after GHRP-2 (C) (both with and without acipimox pretreatment). , data without acipimox pretreatment; •, data with acipimox pretreatment.

View larger version (30K): [in this window] [in a new window]   Figure 4. Basal (t = 0) and peak FFA levels in individual subjects before and after administration of GHRP-2, with (interrupted lines) and without (solid lines) acipimox pretreatment. The interrupted and solid lines represent mean ± SEM. The difference between the basal and peak levels was statistically significant for both conditions (P = 0.01).

	Discussion

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It has previously been demonstrated that GHRP-2 is a very strong GH secretagogue in comparison with GHRH, causing a GH release that is more than 3-fold higher than the GHRH-mediated secretion (26). Furthermore, it was demonstrated that this effect was observed both in men and women of different ages and that the differences in GH secretion between young and old subjects after either of the stimuli persisted. GHRP-2 and GHRH combined had a synergistic effect on GH secretion, and peak GH levels of 40 µg/L were reached in elderly men (26). The present data show that the combination of acipimox and GHRP-2 can still further increase GH secretion in comparison with the reported combined effect of GHRH and GHRP-2 in elderly men. However, although age and body mass index (BMI) of our subjects were comparable with the subjects studied by Bowers (26), the large intraindividual variation in GH response makes it impossible to conclude that combined acipimox/GHRP-2 has a stronger effect on GH secretion than GHRH + GHRP-2. The strong association that we observed between the response after acipimox/GHRP-2 and after GHRP-2 alone indicates an explained variance of 86%, which is much higher than that of the association between the response after acipimox/GHRH and GHRH alone. This is in line with the evidence that responses to GHRPs are less variable than responses to GHRH (27). The associations between GHRP-2 and GHRH-related responses also indicate, that for each subject, stimulated GH release is modulated by other factors such as different levels of somatostatinergic tone. Therefore, the combined administration of acipimox, arginine, and GHRP-2 could be used as a tool to evaluate whether a plateau level of GH secretion can be reached by decreasing somatostatinergic inhibition.

The negative correlations between plasma FFA concentrations and both basal and stimulated GH, in combination with the observation that the administration of 200 µg GHRP-2 increases plasma FFAs, further support the concept of a classic feedback loop between circulating FFAs and pituitary GH secretion. Our data cannot answer the question by which mechanism and/or at which site (pituitary, hypothalamic or elsewhere) this interaction is operative. Previous studies have shown that the inhibitory effect of FFAs is located directly at the pituitary level (21, 28). The present data clearly show that, as GHRH- and GHRP-2-mediated GH release were similarly influenced by reduction of FFA levels, circulating FFAs do not selectively affect the specific receptor for one of these GH secretagogues. Therefore, it might be speculated that FFAs affect pituitary GH release rather than receptor-mediated interactions with GH secretagogues or hypothalamic somatostatin.

It has been suggested that the age-related decline in GH secretion could be explained by the increase in body fat mass associated with aging rather than a direct effect of aging per se (5, 7). The determinants of the activity of the somatotropic axis have been studied extensively, both in rats and in humans. Besides GHRH, somatostatin, putative GHRPs such as ghrelin, and FFAs, other factors such as catecholamines, dopamine, glucocorticoids, insulin, leptin, and sex steroids play a role at different levels, leading to a complex regulation mechanism (3, 10). We evaluated whether parameters reflecting visceral and total body fat mass or measures of insulin resistance were associated with the age-related decline in GH secretion. The observation that no significant correlations could be found should be carefully interpreted because only a small number of subjects were studied and because we excluded subjects who were centrally obese. Furthermore, our subjects had no clinical or biochemical signs of insulin resistance. Our findings are in line with the observation by Pontiroli et al. (18), who observed no significant correlation between stimulated GH release and serum insulin levels.

While the present data show that reduction of FFAs increases GH release, we could also demonstrate a significant rise in circulating FFAs within 30 min after GHRP-2 administration. This acute rise might be the consequence of an acute lipolytic effect of GHRP-2 or another GHRP-2-mediated effect. Previous studies have shown that after sc administration of GH, lipolysis and rise of FFAs occurs after 120 min (29). Taking into account that GHRP receptors are expressed in adipose tissue (30), it is possible that the rapid increase in plasma FFAs after GHRP-2 administration is exerted by a direct effect of this peptide on the adipocytes. Furthermore, it cannot be ruled out that other mechanisms such as GHRP-2-induced co-release of other pituitary hormones such as ACTH or TSH could be responsible for the rapid increase in plasma FFAs after GHRP-2 administration.

In conclusion, the present data demonstrate that GHRP-2-stimulated GH secretion in the elderly can be enhanced by the reduction of circulating FFAs and that, under these circumstances, GHRP-2-mediated GH release is strongly increased in comparison with the effect of GHRH. Furthermore, administration of GHRP-2 induces an acute lipolytic effect. The exact contribution of changes in FFAs to the age-related decline in GH secretion remains to be determined, given the large number of hormonal and metabolic changes associated with aging. Our data show that the pituitary GH secretory capacity in elderly men is still intact, and that the attenuated GH secretion in this population can be overcome by the reduction of FFA.

	Acknowledgments

 
The supply of GHRP-2 from Dr. Cyril Y. Bowers (Tulane University, New Orleans, LA) is gratefully acknowledged.

Received April 8, 2000.

Revised August 2, 2000.

Accepted August 31, 2000.

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