AJP - Regu Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Regul Integr Comp Physiol 286: R693-R698, 2004. First published December 11, 2003; doi:10.1152/ajpregu.00595.2003
0363-6119/04 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
286/4/R693    most recent
00595.2003v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (8)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kok, P.
Right arrow Articles by Pijl, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kok, P.
Right arrow Articles by Pijl, H.

APPETITE, OBESITY AND METABOLISM

Acipimox enhances spontaneous growth hormone secretion in obese women

Petra Kok,1 Madelon M. Buijs,1 Simon W. Kok,1 Inge H. A. P. van Ierssel,1 Marijke Frölich,2 Ferdinand Roelfsema,3 Peter J. Voshol,4 A. Edo Meinders,1 and Hanno Pijl1

1Department of General Internal Medicine, 2Department of Clinical Chemistry, and 3Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, 2300 RC Leiden; and 4Dutch Organization for Applied Scientific Research-Prevention and Health/-Pharma, 2333 AL Leiden, The Netherlands

Submitted 13 October 2003 ; accepted in final form 8 December 2003


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We hypothesized that a high circulating free fatty acid (FFA) concentration is involved in the pathogenesis of hyposomatotropism associated with obesity. To evaluate this hypothesis, 10 healthy premenopausal women (body mass index 33.8 ± 1.0 kg/m2) were studied in the follicular phase of their menstrual cycle at two occasions with a time interval of at least 8 wk, where body weight remained stable. Subjects were randomly assigned to treatment with either acipimox (an inhibitor of lipolysis, 250 mg orally 4 times daily) or placebo in a double-blind crossover design, starting 1 day before admission until the end of the blood sampling period. Blood samples were taken during 24 h with a sampling interval of 10 min for assessment of growth hormone (GH) concentrations, and GH secretion was estimated by deconvolution analysis. Identical methodology was used to study GH secretion in a historical control group of age-matched normal weight women. GH secretion was clearly blunted in obese women (total daily release 66 ± 10 vs. lean controls: 201 ± 23 mU·lVd-1·24 h-1, P = 0.005, where lVd is liter of distribution volume). Acipimox considerably enhanced total (113 ± 50 vs. 66 ± 10 mU·lVd-1·24 h-1, P = 0.02) and pulsatile GH secretion (109 ± 49 vs. 62 ± 30 mU·lVd-1·24 h-1, P = 0.02), but GH output remained lower compared with lean controls. Further analysis did not show any relationship between the effects of acipimox on GH secretion and regional body fat distribution. In conclusion, acipimox unleashes spontaneous GH secretion in obese women. It specifically enhances GH secretory burst mass. This might mean that lowering of systemic FFA concentrations by acipimox modulates neuroendocrine mechanisms that orchestrate the activity of the somatotropic ensemble.

hyposomatotropism; growth hormone kinetics; somatotroph cell function; free fatty acid

SPONTANEOUS PULSATILE growth hormone (GH) release (36, 49) and GH secretion in response to various provocative exogenous stimuli (1, 7, 14) are markedly blunted in obese patients. The mechanism underlying this neuroendocrine feature of obese humans remains elusive.

Obesity is associated with high circulating free fatty acid (FFA) concentrations (11, 21), and FFA have been shown to suppress GH release in humans and animals (5, 6, 13, 19, 27, 41). Thus hyposomatotropism in obese individuals may be brought about by elevated plasma FFAs. Indeed, reduction of circulating FFA levels with acipimox, a powerful antilipolytic drug, considerably enhances GH secretion in response to various secretagogues in obese humans (10, 25, 26, 33, 40). It remains to be established if acipimox also unleashes spontaneous GH release in obese individuals.

Excess fat can be stored in various adipose depots. It appears that neuroendocrine alterations particularly occur in viscerally obese patients (28, 36). Visceral fat is morphologically and functionally distinct from subcutaneous fat in that cellularity and FFA turnover are higher per unit adipose tissue (22, 29, 42, 47). Also, venous output of visceral fat drains directly into the portal system of the liver, while FFAs from subcutaneous fat enter the systemic circulation. FFA infusion into the portal vein enhances pituitary-adrenal axis and sympathetic nervous system activity, whereas systemic FFA infusion does not exert appreciable effects on these neuroendocrine ensembles (2, 15). Thus a high portal FFA flux, brought about by excess visceral fat, may particularly inhibit GH release.

We hypothesized that circulating FFAs are involved in the pathogenesis of hyposomatotropism in obese humans. Therefore, we measured 24-h spontaneous GH release in response to administration of acipimox, a powerful inhibitor of lipolysis, in obese women. To further clarify the role of FFA released by visceral fat, we sought to determine the relationship between the effects of acipimox and the size of various adipose depots.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects

Ten healthy obese premenopausal women were enrolled in our study. Subjects were recruited taking body fat distribution into account. Conditions for participation were verified through medical screening, including medical history, physical examination, standard laboratory hematology, blood chemistry, urine and pregnancy tests, and anthropometric measurements. A historical control group of lean women matched for age was included for comparison of GH secretion data with those in obese women. All obese subjects and the age-matched lean controls had an unremarkable medical history. Subjects were nonalcoholic, nonsmoking, and were not taking any medication, including hormonal contraception. All subjects gave written acknowledgement of informed consent.

Body Composition

Total body fat mass (TBFM) was quantified on a separate day preceding the first study occasion using dual-energy X-ray absorptiometry (3). Visceral and subcutaneous adipose tissue areas were assessed by magnetic resonance imaging (MRI) as described before (24), using a multislice fast spin echo sequence (Gyroscan-T5 whole body scanner, 0.5 T, Philips Medical Systems, Best, The Netherlands). MRI images were analyzed independently by two observers.

Drugs

Subjects were randomly assigned to 250 mg acipimox or placebo in a double-blind crossover design by an independent investigator. Drug and placebo were taken four times daily (total 10 tablets) at 0700, 1300, 1900, and 0100 starting the day before admission until the end of the blood sampling period.

Diet

To limit confounding by nutritional factors, a dietician prescribed a eucaloric diet for each patient, taking basal energy requirement (calculated by the Harris-Benedict formula) and physical activity into account. The macronutrient composition of the diet was exactly the same for each patient at both study occasions. The diet consisted of bread meals, prepared and supplied by the research center. Meals were served according to a fixed time schedule: breakfast at 0730, lunch at 1300, and dinner at 1900, and were consumed within limited time periods.

Clinical Protocol

The Medical Ethics Committee of the Leiden University Medical Center approved the protocol for both study groups. Apart from the fact that controls did not receive acipimox treatment, the procedures and the clinical setup of the experiments were exactly the same in obese subjects and controls. Subjects were admitted to the Clinical Research Unit of the Department of General Internal Medicine in the early follicular stage of their menstrual cycle at two separate occasions at 1600 with an interval of at least 8 wk. A cannula for blood sampling was inserted into an antecubital vein, and blood samples for basal parameters were withdrawn. The cannula was attached to a three-way stopcock and kept patent by a continuous saline infusion. Blood samples were taken with S-monovetten (Sarstedt, Etten-Leur, The Netherlands). Twenty four hour blood sampling started at 1800, and blood was collected at 10-min intervals for determination of GH concentrations. Plasma FFA levels were measured every 6 h. Plasma FFA concentrations were not measured in the historical control group. Subjects remained recumbent, except for bathroom visits. Lights were switched off at 2300. Vital signs were recorded at regular time intervals. The clinical setup was the same during both occasions apart from the subject receiving the alternative treatment (acipimox or placebo).

Assays

Blood sample handling and GH assays were performed using the same methodology in obese subjects and controls. Each tube, except the serum tubes, was immediately chilled on ice. Samples were centrifuged at 4,000 rpm at 4°C during 20 min, within 60 min of sampling. Subsequently, plasma was divided into separate aliquots and frozen at -80°C until assays were performed. GH concentrations were measured with a sensitive time-resolved fluoroimmunoassay (Wallac, Turku, Finland) specific for the 22-kDa GH protein. The assay uses recombinant human GH as standard (Genotropin, Pharmacia and Upjohn, Uppsala, Sweden), which is calibrated against World Health Organization First International Reference Preparation (80-505). The limit of detection is 0.03 mU/l. Intra-assay coefficients of variation (CV) were 1.6-8.4% in the concentration range 0.26-47 mU/l, with corresponding interassay CVs of 2.0-9.9%.

The total serum insulin-like growth factor I (IGF-I) concentration was determined by RIA after extraction and purification on ODS-silica columns (Incstar, Stillwater, MN). The interassay CV was <11.8%. The detection limit was 1.5 nmol/l. Age-related normative data were determined in the same laboratory. FFA levels were determined using a NEFA-C FFA kit (Wako Chemicals, Neuss, Germany). The detection limit was 0.03 mmol/l, and the inter- and intra-assay CVs were 1.1 and 2.6%, respectively.

Calculations and Statistics

Deconvolution analysis. Multiparameter deconvolution analysis was used to determine kinetic and secretory parameters of 24-h spontaneous GH secretion, calculated from GH plasma concentrations. An initial guess of the secretion profile for waveform-independent estimates of GH secretion was created with Pulse 2, an automated pulse detection program. Subsequent analysis with a waveform-dependent multiparameter deconvolution method was performed as described previously, using a first component half-life of 3.5 min, a second component half-life of 20.8 min, and a relative contribution of the slow component to the total elimination of 0.68 (50, 51). This technique thus estimates the rate of basal release, the number and mass of randomly ordered secretory bursts, and the subject-specific half-life. The daily pulsatile GH secretion is the product of secretory burst frequency and mean mass of GH released per event. Total GH secretion is the sum of basal and pulsatile secretion.

Approximate entropy. Approximate entropy (ApEn) is a scale- and model-independent statistic, applicable to a wide variety of physiological and clinical time-series data (16, 38, 39). ApEn quantitates the orderliness or regularity of serial GH concentrations over 24 h. Normalized ApEn parameters of m = 1 (test range) and r = 20% (threshold) of the intraseries SD were used, as described previously (37). Hence, this member of the ApEn family is designated ApEn(1,20%). The ApEn metric evaluates the consistency of recurrent subordinate (nonpulsatile) patterns in a time series and thus yields information distinct from and complementary to cosinor and deconvolution (pulse) analyses (53). Higher absolute ApEn values denote greater relative randomness of hormone patterns. Data are presented as absolute ApEn values and normalized ApEn ratios, defined by the mean ratio of absolute ApEn to that of 1,000 randomly shuffled versions of the same series (54).

Statistics. TBFM is presented as a percentage of total body weight. Subcutaneous fat mass (SFM) and visceral fat mass (VFM) were expressed as a percentage of total fat mass. To determine the effect of acipimox on daily GH secretion, numeric outcomes of deconvolution analysis and the ApEn metric were statistically analyzed using one-way ANOVA.

Differences between GH kinetic parameters between lean controls and obese women were analyzed using Student's t-test for unpaired samples. Multiple regression analysis, using TBFM, VFM, and SFM as independent variables, was done to determine specific correlations between measures of body fat distribution and GH secretory and kinetic parameters. All data are given as means ± SE, and signifi-cance level was set at 0.05


   RESULTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subjects

Ten obese women [age 35.8 ± 2.0 yr, body mass index (BMI) 33.8 ± 1.0 kg/m2] and seven lean controls (age 35.1 ± 3.0 yr, BMI 21.5 ± 0.5 kg/m2) were included. Body weight remained stable from 3 mo before until the end of the study period.

Effect of Acipimox on Spontaneous GH Secretion

Mean 24-h plasma FFA levels were reduced during acipimox treatment in all subjects (placebo 0.52 ± 0.04 vs. acipimox 0.40 ± 0.03 mmol/l, P = 0.005). Under placebo conditions, GH kinetic and secretory parameters were significantly lower in the obese subjects compared with the age-matched lean controls. Acipimox treatment significantly increased burst amplitude, burst mass, and pulsatile and total daily GH production, while burst frequency, half-life, secretory half-duration, and basal production were not significantly affected (Fig. 1). However, acipimox did not restore GH secretion to reference levels as determined in lean controls. Mean 24-h IGF-I levels were not affected by acipimox (Table 1). An overview of GH secretory and kinetic parameters and reference values of GH secretory parameters in age-matched premenopausal normal weight women, as determined in the control group, is given in Table 1. A graphical illustration of a representative 24-h GH concentration dataset and corresponding secretory profile is shown in Fig. 2.



View larger version (30K):
[in this window]
[in a new window]
  		Fig. 1. Various parameters of spontaneous pulsatile growth hormone (GH) release during placebo (plac) and acipimox (acip) in obese women. P values of the difference between means during placebo vs. acipimox treatment determined by 1-way ANOVA are presented. lVd, Liter of distribution volume.

 

View this table:
[in this window]
[in a new window]
  		Table 1. Effect of acipimox on 24-h GH secretory parameters in obese subjects

 


View larger version (19K):
[in this window]
[in a new window]
  		Fig. 2. A: example of plasma GH concentration of 1 obese subject on placebo or acipimox treatment and a lean control of similar age. B: corresponding secretion rate profiles before and during acipimox treatment in the obese woman.

 

Impact of Body Fat Distribution

The obese subjects had a BMI of 33.8 ± 0.96 (range 31.0-39.4) kg/m2 and a waist-to-hip ratio of 0.85 ± 0.01 (range 0.75-0.92) and their TBFM (% of total body wt) was 40.6 ± 1.1 (range 36.9-46.3)%. The sizes of their visceral and subcutaneous fat area were 392 ± 30 (range 274-539) cm2 and 1,348 ± 58 (range 1,162-1,709) cm2, respectively.

Multiple regression analysis, including TBFM, VFM, and SFM as independent variables, showed no significant correlation (R2 = 0.00, P = 0.48) between the size of visceral fat mass and the increase of total GH production during acipimox treatment.

ApEn

ApEn ratios of plasma GH concentration time series were similar in obese and normal weight women. ApEn ratios were not affected by acipimox (Table 1). Body fat distribution did not impact orderliness of the GH time series data either.


   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Here we show that acipimox unleashes spontaneous GH secretion in obese women. The drug particularly enhanced GH secretory burst mass, whereas burst frequency and basal GH secretion were largely unaffected. However, total daily GH production remained significantly lower than in normal weight controls. The distribution of excess fat over the various depots does not appear to impact the effect of acipimox on GH secretion in obese individuals.

It has been repeatedly reported that the profound reduction of spontaneous GH secretion that is invariably observed in obese humans is primarily brought about by a diminution of secretory burst mass (20, 52). The present data therefore suggest that acipimox partially restores this primary neuroendocrine anomaly that underlies hyposomatotropism in obesity. GH-releasing hormone (GHRH) input is a critical determinant of GH secretory burst mass, whereas other components of the somatotrophic ensemble appear to control burst frequency and basal secretion (43). In vitro data show that incorporation of cis-unsaturated fatty acids into the plasma membrane of GH3 cells disrupts signal transduction pathways that are pivotal for GHRH-induced GH release (34, 35). Thus acipimox may enhance somatotroph sensitivity to GHRH feedforward inputs through lowering of circulating (cis-unsaturated) FFA and thereby specifically stimulate GH secretory burst mass, an inference that is in keeping with our observations.

A high portal FFA flux, released by excess visceral adipose tissue directly into the portal vein, could be responsible for the diminution of GH release in viscerally obese humans (3). In this scenario, one would expect acipimox to exert its greatest effect on GH release in humans with large visceral fat stores. Our data are not in keeping with this postulate. However, the size of our study population was rather small, which considerably limits the statistical power to detect potential correlations in regression analyses.

Although acipimox considerably enhanced GH secretion in obese subjects, it did not fully restore GH output to levels observed in normal weight controls. In this context, it seems prudent to emphasize that we used historical controls, which may limit the comparability of the data, although the clinical setup, the applied assays, and mathematical techniques for data analysis were identical in both groups.

Other physiological cues than FFA may also have affected GH release in our study. For example, insulin can blunt GH release (8, 31). Acipimox can lower plasma insulin (48) and thereby enhance GH secretion. Also, high circulating insulin levels in our obese subjects might explain their persistently lower GH secretion rate with and without acipimox treatment. Unfortunately, we did not measure insulin levels to further evaluate these possibilities. Another potential mechanistic explanation for the profound impact of acipimox on GH secretion may relate to activation of dopaminergic neural circuits. Acipimox is a nicotinic acid derivative, and nicotinic acid can activate dopaminergic neurons (9, 17, 18, 23, 30, 46). Dopamine promotes (secretagogue induced) GH release through activation of dopamine D2 receptors in rats and humans (4, 12, 32, 44, 45). Thus acipimox may also stimulate GH output through neural pathways.

In conclusion, the present data show that acipimox acutely promotes spontaneous GH output in obese humans. It specifically enhances GH secretory burst mass, which might support the notion that acipimox improves GHRH's ability to induce GH release by pituitary somatotrophs. The mechanism through which acipimox exerts its effect on GH secretion in obese humans remains elusive.


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. Pijl, Leiden Univ. Medical Center, Dept. of Endocrinology, C4-83, PO Box 9600, 2300 RC Leiden, The Netherlands (E-mail: h.pijl{at}lumc.nl).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Alvarez P, Isidro L, Leal-Cerro A, Casanueva FF, Dieguez C, and Cordido F. Effect of withdrawal of somatostatin plus GH-releasing hormone as a stimulus of GH secretion in obesity. Clin Endocrinol (Oxf) 56: 487-492, 2002.[CrossRef][Medline]
  2. Benthem L, Keizer K, Wiegman CH, De Boer SF, Strubbe JH, Steffens AB, Kuipers F, and Scheurink AJ. Excess portal venous long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation. Am J Physiol Endocrinol Metab 279: E1286-E1293, 2000.[Abstract/Free Full Text]
  3. Blake GM and Fogelman I. Technical principles of dual energy x-ray absorptiometry. Semin Nucl Med 27: 210-228, 1997.[CrossRef][ISI][Medline]
  4. Bosma PT, Kolk SM, Rebers FE, Lescroart O, Roelants I, Willems PH, and Schulz RW. Gonadotrophs but not somatotrophs carry gonadotrophin-releasing hormone receptors: receptor localisation, intracellular calcium, and gonadotrophin and GH release. J Endocrinol 152: 437-446, 1997.[Abstract]
  5. Briard N, Rico-Gomez M, Guillaume V, Sauze N, Vuaroqueaux V, Dadoun F, Le Bouc Y, Oliver C, and Dutour A. Hypothalamic mediated action of free fatty acid on growth hormone secretion in sheep. Endocrinology 139: 4811-4819, 1998.[Abstract/Free Full Text]
  6. Casanueva FF, Villanueva L, Dieguez C, Diaz Y, Cabranes JA, Szoke B, Scanlon MF, Schally AV, and Fernandez Cruz A. Free fatty acids block growth hormone (GH) releasing hormone-stimulated GH secretion in man directly at the pituitary. J Clin Endocrinol Metab 65: 634-642, 1987.[Abstract]
  7. Castro RC, Vieira JG, Chacra AR, Besser GM, Grossman AB, and Lengyel AM. Pyridostigmine enhances, but does not normalise, the GH response to GH-releasing hormone in obese subjects. Acta Endocrinol 122: 385-390, 1990.
  8. Ceda GP, Hoffman AR, Silverberg GD, Wilson DM, and Rosenfeld RG. Regulation of growth hormone release from cultured human pituitary adenomas by somatomedins and insulin. J Clin Endocrinol Metab 60: 1204-1209, 1985.[Abstract]
  9. Charpantier E, Barneoud P, Moser P, Besnard F, and Sgard F. Nicotinic acetylcholine subunit mRNA expression in dopaminergic neurons of the rat substantia nigra and ventral tegmental area. Neuroreport 9: 3097-3101, 1998.[ISI][Medline]
  10. Cordido F, Peino R, Penalva A, Alvarez CV, Casanueva FF, and Dieguez C. Impaired growth hormone secretion in obese subjects is partially reversed by acipimox-mediated plasma free fatty acid depression. J Clin Endocrinol Metab 81: 914-918, 1996.[Abstract]
  11. Couillard C, Bergeron N, Prud'homme D, Bergeron J, Tremblay A, Bouchard C, Mauriege P, and Despres JP. Postprandial triglyceride response in visceral obesity in men. Diabetes 47: 953-960, 1998.[Abstract]
  12. Diaz-Torga G, Feierstein C, Libertun C, Gelman D, Kelly MA, Low MJ, Rubinstein M, and Becu-Villalobos D. Disruption of the D2 dopamine receptor alters GH and IGF-I secretion and causes dwarfism in male mice. Endocrinology 143: 1270-1279, 2002.[Abstract/Free Full Text]
  13. Estienne MJ, Schillo KK, Hileman SM, Green MA, Hayes SH, and Boling JA. Effects of free fatty acids on luteinizing hormone and growth hormone secretion in ovariectomized lambs. Endocrinology 126: 1934-1940, 1990.[Abstract]
  14. Ghigo E, Procopio M, Boffano GM, Arvat E, Valente F, Maccario M, Mazza E, and Camanni F. Arginine potentiates but does not restore the blunted growth hormone response to growth hormone-releasing hormone in obesity. Metabolism 41: 560-563, 1992.[CrossRef][ISI][Medline]
  15. Grekin RJ, Dumont CJ, Vollmer AP, Watts SW, and Webb RC. Mechanisms in the pressor effects of hepatic portal venous fatty acid infusion. Am J Physiol Regul Integr Comp Physiol 273: R324-R330, 1997.[Abstract/Free Full Text]
  16. Hartman ML, Pincus SM, Johnson ML, Matthews DH, Faunt LM, Vance ML, Thorner MO, and Veldhuis JD. Enhanced basal and disorderly growth hormone secretion distinguish acromegalic from normal pulsatile growth hormone release. J Clin Invest 94: 1277-1288, 1994.[ISI][Medline]
  17. Hirokawa Y, Morie T, Yamazaki H, Yoshida N, and Kato S. A novel series of N-(hexahydro-1,4-diazepin-6-yl) and N-(hexahydroazepin-3-yl) benzamides with high affinity for 5-HT3 and dopamine D2 receptors. Bioorg Med Chem Lett 8: 619-624, 1998.[CrossRef][Medline]
  18. Hirokawa Y, Yoshida N, and Kato S. Synthesis of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)nicotinamides and their affinities for 5-HT3 and dopamine D2 receptors. Bioorg Med Chem Lett 8: 1551-1554, 1998.[CrossRef][Medline]
  19. Imaki T, Shibasaki T, Shizume K, Masuda A, Hotta M, Kiyosawa Y, Jibiki K, Demura H, Tsushima T, and Ling N. The effect of free fatty acids on growth hormone (GH)-releasing hormone-mediated GH secretion in man. J Clin Endocrinol Metab 60: 290-293, 1985.[Abstract]
  20. Iranmanesh A, South S, Liem AY, Clemmons D, Thorner MO, Weltman A, and Veldhuis JD. Unequal impact of age, percentage body fat, and serum testosterone concentrations on the somatotrophic, IGF-I, and IGF-binding protein responses to a three-day intravenous growth hormone-releasing hormone pulsatile infusion in men. Eur J Endocrinol 139: 59-71, 1998.[Abstract]
  21. Jensen MD, Haymond MW, Rizza RA, Cryer PE, and Miles JM. Influence of body fat distribution on free fatty acid metabolism in obesity. J Clin Invest 83: 1168-1173, 1989.[ISI][Medline]
  22. Jensen MD and Johnson CM. Contribution of leg and splanchnic free fatty acid (FFA) kinetics to postabsorptive FFA flux in men and women. Metabolism 45: 662-666, 1996.[CrossRef][ISI][Medline]
  23. Jones IW, Bolam JP, and Wonnacott S. Presynaptic localisation of the nicotinic acetylcholine receptor {beta}2 subunit immunoreactivity in rat nigrostriatal dopaminergic neurones. J Comp Neurol 439: 235-247, 2001.[CrossRef][ISI][Medline]
  24. Langendonk JG, Pijl H, Toornvliet AC, Burggraaf K, Frolich M, Schoemaker RC, Doornbos J, Cohen AF, and Meinders AE. Circadian rhythm of plasma leptin levels in upper and lower body obese women: influence of body fat distribution and weight loss. J Clin Endocrinol Metab 83: 1706-1712, 1998.[Abstract/Free Full Text]
  25. Lee EJ, Nam SY, Kim KR, Lee HC, Cho JH, Nam MS, Song YD, Lim SK, and Huh KB. Acipimox potentiates growth hormone (GH) response to GH-releasing hormone with or without pyridostigmine by lowering serum free fatty acid in normal and obese subjects. J Clin Endocrinol Metab 80: 2495-2498, 1995.[Abstract]
  26. Maccario M, Procopio M, Grottoli S, Oleandri SE, Boffano GM, Taliano M, Camanni F, and Ghigo E. Effects of acipimox, an antilipolytic drug, on the growth hormone (GH) response to GH-releasing hormone alone or combined with arginine in obesity. Metabolism 45: 342-346, 1996.[CrossRef][ISI][Medline]
  27. Maccario M, Procopio M, Loche S, Cappa M, Martina V, Camanni F, and Ghigo E. Interaction of free fatty acids and arginine on growth hormone secretion in man. Metabolism 43: 223-226, 1994.[CrossRef][ISI][Medline]
  28. Marin P. Cortisol secretion in relation to body fat distribution in obese premenopausal women. Metabolism 41: 882-886, 1992.[CrossRef][ISI][Medline]
  29. Martin ML and Jensen MD. Effects of body fat distribution on regional lipolysis in obesity. J Clin Invest 88: 609-613, 1991.[ISI][Medline]
  30. Marubio LM, Gardier AM, Durier S, David D, Klink R, Arroyo-Jimenez MM, McIntosh JM, Rossi F, Champtiaux N, Zoli M, and Changeux JP. Effects of nicotine in the dopaminergic system of mice lacking the {alpha}4 subunit of neuronal nicotinic acetylcholine receptors. Eur J Neurosci 17: 1329-1337, 2003.[CrossRef][ISI][Medline]
  31. Melmed S. Insulin suppresses growth hormone secretion by rat pituitary cells. J Clin Invest 73: 1425-1433, 1984.[ISI][Medline]
  32. Mueller GP, Twohy CP, Chen HT, Advis JP, and Meites J. Effect of L-tryptophan and restraint stress on hypothalmic and brain serotonin turnover, and pituitary TSH and prolactin release in rats. Life Sci 18: 715-724, 1976.[CrossRef][ISI][Medline]
  33. Nam SY, Lee Kim KR, Lee HC, Nam MS, Cho JH, and Huh KB. Long-term administration of acipimox potentiates growth hormone response to growth hormone-releasing hormone by decreasing serum free fatty acid in obesity. Metabolism 45: 594-597, 1996.[CrossRef][ISI][Medline]
  34. Perez FR, Camina JP, Zugaza JL, Lage M, Casabiell X, and Casanueva FF. cis-FFA do not alter membrane depolarization but block Ca2+ influx and GH secretion in KCl-stimulated somatotroph cells. Suggestion for a direct cis-FFA perturbation of the Ca2+ channel opening. Biochim Biophys Acta 1329: 269-277, 1997.[Medline]
  35. Perez FR, Casabiell X, Camina JP, Zugaza JL, and Casanueva FF. cis-Unsaturated free fatty acids block growth hormone and prolactin secretion in thyrotropin-releasing hormone-stimulated GH3 cells by perturbing the function of plasma membrane integral proteins. Endocrinology 138: 264-272, 1997.[Abstract/Free Full Text]
  36. Pijl H, Langendonk JG, Burggraaf J, Frolich M, Cohen AF, Veldhuis JD, and Meinders AE. Altered neuroregulation of growth hormone secretion in viscerally obese premenopausal women. J Clin Endocrinol Metab 86: 5509-5515, 2001.[Abstract/Free Full Text]
  37. Pincus SM. Approximate entropy as a measure of system complexity. Proc Natl Acad Sci USA 88: 2297-2301, 1991.[Abstract/Free Full Text]
  38. Pincus SM. Quantification of evolution from order to randomness in practical time series analysis. Methods Enzymol 240: 68-89, 1994.[ISI][Medline]
  39. Pincus SM and Keefe DL. Quantification of hormone pulsatility via an approximate entropy algorithm. Am J Physiol Endocrinol Metab 262: E741-E754, 1992.[Abstract/Free Full Text]
  40. Pontiroli AE, Manzoni MF, Malighetti ME, and Lanzi R. Restoration of growth hormone (GH) response to GH-releasing hormone in elderly and obese subjects by acute pharmacological reduction of plasma free fatty acids. J Clin Endocrinol Metab 81: 3998-4001, 1996.[Abstract/Free Full Text]
  41. Quabbe HJ, Bunge S, Walz T, and Bratzke B. Plasma glucose and free fatty acids modulate the secretion of growth hormone, but not prolactin, in the rhesus and Java monkey. J Clin Endocrinol Metab 70: 908-915, 1990.[Abstract]
  42. Reynisdottir S, Dauzats M, Thorne A, and Langin D. Comparison of hormone-sensitive lipase activity visceral and subcutaneous human adipose tissue. J Clin Endocrinol Metab 82: 4162-4166, 1997.[Abstract/Free Full Text]
  43. Roelfsema F, Biermasz NR, Veldman RG, Veldhuis JD, Frolich M, Stokvis-Brantsma WH, and Wit JM. Growth hormone (GH) secretion in patients with an inactivating defect of the GH-releasing hormone (GHRH) receptor is pulsatile: evidence for a role for non-GHRH inputs into the generation of GH pulses. J Clin Endocrinol Metab 86: 2459-2464, 2001.[Abstract/Free Full Text]
  44. Schilling JC, Adamus WS, and Palluk R. Neuroendocrine and side effect profile of pramipexole, a new dopamine receptor agonist, in humans. Clin Pharmacol Ther 51: 541-548, 1992.[ISI][Medline]
  45. Schwinn G, Schwarck H, McIntosh C, Milstrey HR, Willms B, and Kobberling J. Effect of the dopamine receptor blocking agent pimozide on the growth hormone response to arginine and exercise and on the spontaneous growth hormone fluctuations. J Clin Endocrinol Metab 43: 1183-1185, 1976.[Abstract]
  46. Serova L and Sabban EL. Involvement of {alpha}7 nicotinic acetylcholine receptors in gene expression of dopamine biosynthetic enzymes in rat brain. J Pharmacol Exp Ther 303: 896-903, 2002.[Abstract/Free Full Text]
  47. Tchkonia T, Giorgadze N, Pirtskhalava T, Tchoukalova Y, Karagiannides I, Forse RA, DePonte M, Stevenson M, Guo W, Han J, Waloga G, Lash TL, Jensen MD, and Kirkland JL. Fat depot origin affects adipogenesis in primary cultured and cloned human preadipocytes. Am J Physiol Regul Integr Comp Physiol 282: R1286-R1296, 2002.[Abstract/Free Full Text]
  48. Vaag A, Skott P, Damsbo P, Gall MA, Richter EA, and Beck-Nielsen H. Effect of the antilipolytic nicotinic acid analogue acipimox on whole-body and skeletal muscle glucose metabolism in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 88: 1282-1290, 1991.[ISI][Medline]
  49. Vahl N, Jorgensen JO, Skjaerbaek C, Veldhuis JD, Orskov H, and Christiansen JS. Abdominal adiposity rather than age and sex predicts mass and regularity of GH secretion in healthy adults. Am J Physiol Endocrinol Metab 272: E1108-E1116, 1997.[Abstract/Free Full Text]
  50. Veldhuis JD, Carlson ML, and Johnson ML. The pituitary gland secretes in bursts: appraising the nature of glandular secretory impulses by simultaneous multiple-parameter deconvolution of plasma hormone concentrations. Proc Natl Acad Sci USA 84: 7686-7690, 1987.[Abstract/Free Full Text]
  51. Veldhuis JD and Johnson ML. Deconvolution analysis of hormone data. Methods Enzymol 210: 539-575, 1992.[ISI][Medline]
  52. Veldhuis JD, Liem AY, South S, Weltman A, Weltman J, Clemmons DA, Abbott R, Mulligan T, Johnson ML, and Pincus S. Differential impact of age, sex steroid hormones, and obesity on basal vs. pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay. J Clin Endocrinol Metab 80: 3209-3222, 1995.[Abstract]
  53. Veldhuis JD and Pincus SM. Orderliness of hormone release patterns: a complementary measure to conventional pulsatile and circadian analyses. Eur J Endocrinol 138: 358-362, 1998.[CrossRef][ISI][Medline]
  54. Veldhuis JD, Straume M, Iranmanesh A, Mulligan T, Jaffe C, Barkan A, Johnson ML, and Pincus S. Secretory process regularity monitors neuroendocrine feedback and feedforward signaling strength in humans. Am J Physiol Regul Integr Comp Physiol 280: R721-R729, 2001.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Appl. Physiol.Home page
K. A. Stokes, C. Tyler, and K. L. Gilbert
The growth hormone response to repeated bouts of sprint exercise with and without suppression of lipolysis in men
J Appl Physiol, March 1, 2008; 104(3): 724 - 728.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
M. H. Vickers, P. L. Hofman, P. D. Gluckman, P. E. Lobie, and W. S. Cutfield
Combination therapy with acipimox enhances the effect of growth hormone treatment on linear body growth in the normal and small-for-gestational-age rat
Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1212 - E1219.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
M. O. van Aken, A. M. Pereira, M. Frolich, J. A. Romijn, H. Pijl, J. D. Veldhuis, and F. Roelfsema
Growth hormone secretion in primary adrenal Cushing's syndrome is disorderly and inversely correlated with body mass index
Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E63 - E70.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
286/4/R693    most recent
00595.2003v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (8)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kok, P.
Right arrow Articles by Pijl, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kok, P.
Right arrow Articles by Pijl, H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2004 by the American Physiological Society.