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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 1 312-316
Copyright © 2003 by The Endocrine Society

Original Article

The Inhibition of Growth Hormone Secretion Presented in Obesity Is Not Mediated by the High Leptin Levels: A Study in Human Leptin Deficiency Patients

Metin Ozata, Carlos Dieguez and Felipe F. Casanueva

Endocrine Section, Complejo Hospitalario Universitario de Santiago, and Departments of Medicine (F.F.C.) and Physiology (C.D.), University of Santiago de Compostela, E-15780 Santiago de Compostela, Spain; and Department of Endocrinology, Gulhane School of Medicine (M.O.), T-06018 Etlik-Ankara, Turkey

Address all correspondence and requests for reprints to: Dr. F. F. Casanueva, P.O. Box 563, E-15780 Santiago de Compostela, Spain. E-mail: endocrine{at}usc.es.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
GH secretion is regulated by hypothalamic and peripheral hormones under a very complex interplay. Superimposed on this regulation, signals of a metabolic nature connect GH secretion with the metabolic and energetic homeostasis of a given individual. GH secretion is enhanced in malnutrition and is severely impeded in obesity, but no information is available to explain why GH secretion is severely impeded or blocked in excess adiposity.

Obesity is associated with high plasma levels of leptin, and leptin participates at the hypothalamic and pituitary levels in the regulation of GH secretion. Thus, it has been postulated that the inhibitory action of obesity on GH discharge may be mediated by excess leptin levels. The only situation in which obesity does not parallel leptin values is the rare case of morbid obesity due to leptin deficiency caused by missense mutation of the leptin gene. To understand the causes of GH blockade presented in obesity, patients with both homozygous and heterozygous mutations of the leptin gene and matched controls for both sex and body mass index (BMI) were studied.

Three homozygous and 5 heterozygous patients with leptin gene mutations as well as 13 control subjects were studied. In all subjects basal levels of leptin and GH values stimulated by the combined administration of GHRH plus GH-releasing peptide-6 (GHRP-6) were analyzed. To analyze the effects of obesity and leptin levels, 5 groups were designed, all them matched by sex and adiposity. The number of subjects (n), leptin levels in micrograms per liter, and adiposity in BMI were as follows: nonobese subjects: n = 5, BMI = 22.1 ± 0.9 kg/m2, leptin = 5.4 ± 0.9; heterozygous patients: n = 5, BMI = 27.0 ± 1.0 kg/m2, leptin = 2.3 ± 0.1; controls for the heterozygous group: n = 5, BMI = 24.7 ± 1.1 kg/m2, leptin = 5.7 ± 1.2; homozygous patients: n = 3, BMI = 54.4 ± 0.2 kg/m2, leptin = 1.0 ± 0.2; and controls for the homozygous group: n = 3, BMI = 50.3 ± 2.0 kg/m2, leptin = 35.0 ± 6.6. In these matched groups, the GHRH- and GHRP-6-stimulated GH secretion (mean peak ± SE; micrograms per liter) was: nonobese, 86.8 ± 8.9 [significantly higher than heterozygous (28.6 ± 4.9) and control for heterozygous (39.9 ± 10.4)]; homozygous group, 9.4 ± 3.0; control for homozygous, 9.3 ± 1.0 (significantly lower than the heterozygous, control for heterozygous, and nonobese groups). Hence, it appeared that GH discharge was negatively conditioned by adiposity and was not influenced by leptin levels.

To further analyze this observation, a correlation analysis showed that GH peaks were negatively correlated with BMI in the 13 control subjects as well as in the 8 leptin-deficient patients. On the contrary, the GH peaks were negatively correlated with leptin levels in controls, but showed the opposite pattern in homo- and heterozygous patients.

In conclusion, the GH secretion blockade, which is characteristic of obese states, is due to adiposity or some factor linked to adiposity, but not to elevated plasma leptin levels.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE CONTROL OF GH secretion resides in the interplay of hypothalamic and peripheral hormones such as GHRH, somatostatin, IGF-I, and the recently discovered GH-stimulant hormone, ghrelin (1). Superimposed over this regulation is a highly complex network of peripheral signals of metabolic nature, such as free fatty acids (FFA), amino acids, carbohydrates, keto-acids, and possible metabolic by-products with a poorly understood regulatory activity (2, 3). GH is the only pituitary hormone that is under such a complex regulation by metabolism and that, in turn, exerts powerful actions over peripheral metabolism, a fact that earned this hormone the name of somatotropic hormone (4).

In this metabolic context, changes in body weight are immediately reflected in the pattern of both spontaneous and stimulated GH secretion (5, 6), a fact that is evident in situations of low body weight due to malnutrition, which are associated with enhanced GH secretion (7, 8, 9, 10). Interestingly, fasting leads to the elimination of gender-based differences in both the pattern of GH secretion and the plasma circulating levels of leptin (10). The contrary situation appears in obesity, in which basal GH secretion is severely reduced, and the GH discharge to all known provocative stimuli is either impeded or blocked (11, 12, 13, 14, 15, 16, 17). Despite the considerable interest in unraveling the basic mechanism by way of which obesity reduces GH secretion, no explanation is currently available and putatively responsible for this inhibition, as FFA, somatostatinergic tone, and IGF-I levels have failed to fully explain the problem (5).

Leptin, the adipocyte produced hormone implicated in energy homeostasis (18), is severely elevated in obesity (19). In fact, it has been postulated that common cases of obesity are not due to the absence of leptin, but, rather, to the low responsiveness of hypothalamic leptin receptors to the signal (20, 21). On the other hand, leptin plays a significant role in GH regulation (22, 23, 24), at least in experimental animals. Based on the above data and the fact that leptin paralleled adiposity, it has been postulated that the GH reduction observed in obesity may be transmitted by a leptin excess acting at hypothalamic level (5).

In the rare cases of massive obesity due to leptin mutation, obesity develops due to an absence of circulating leptin (25, 26). These are the only situations in which a divergence between leptin and adiposity ensues. To understand the mechanisms of GH reduction in obesity we studied a group of patients with obesity caused by leptin deficiency who were challenged with the effective stimulus GHRH plus GH-releasing peptide-6 (GHRP-6). The targets of the work were 2-fold: firstly to study the stimulated GH secretion in obese subjects with either severe leptin deficiency or normal leptin levels, and secondly to understand the role of leptin in subjects with lower than normal leptin levels.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The subjects of this study were eight patients with human leptin deficiency caused by a missense mutation of the leptin gene. Three subjects (two women and one man) were homozygous mutations; they were aged 23–36 yr, with body mass indexes (BMIs) of 54.8, 54.1, and 54.3 kg/m2 (homozygous group). Five subjects (two women and three men) had heterozygous mutations in the leptin gene; they were aged 24–50 yr, with BMIs ranging from 24.4–29.2 kg/m2 (heterozygous group). Thirteen obese and nonobese subjects were selected as control groups and were matched by sex and BMI with the patients. In particular, three subjects (two women and one man), aged 21–35 yr, acted as controls for the homozygous patients; they had BMIs of 47.6, 49.1, and 54.4 kg/m2 (control-homozygous). Five subjects (two women and three men), aged 23–50 yr, acted as controls for the heterozygous patients, with a mean BMI of 24.7 ± 1.1 kg/m2 (control-heterozygous). A third control group of nonobese subjects (three women and two men), aged 21–59 yr with BMI ranging from 20.2–24.6 kg/m2, was also studied (nonobese). Homozygous patients all had morbid obesity and hypogonadism and were diagnosed as previously described (25, 26). No endocrine dysfunction was observed in the heterozygous group. With the exception of some of the controls being overweight or obese, all were healthy and they were selected on the basis of being matched for sex and BMI with the patients and of having nonpresenting actual or past history of endocrinological disease. Menstruating women were studied in the follicular phase of the ovarian cycle. The study was approved by the hospital ethical committee, and informed consent was obtained previously from all participants.

The heights and weights of all subjects were measured, and their BMIs were calculated (weight in kilograms divided by squared height in meters), and blood count and standard biochemical analysis were performed.

Tests started at 0800 h after an overnight fast, with the subjects recumbent. An indwelling catheter was placed in a forearm vein and was kept permeable with a slow infusion of 150 mmol/liter NaCl. The first blood sample was obtained at 30 min before treatment. After obtaining samples for leptin determination, the GH stimulus was administered at 0 min, and additional blood samples were obtained at appropriate intervals. Leptin-deficient patients and control subjects underwent the combined administration of GHRH and GHRP-6 to assess the GH secretory status (27). The so-called combined GHRH and GHRP-6 test consisted of an iv bolus injection of 1 µg/kg GHRH [GRF-(1–29)-NH2, Geref Serono, Madrid, Spain], immediately followed by an iv bolus injection of 1 µg/kg GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) obtained from CLINALFA (Laufelfinger, Switzerland). After centrifugation, plasma samples were stored at -20 C until analysis.

Serum leptin levels were measured in duplicate by RIA for leptin using commercial kits (Human Leptin RIA, Linco Research, Inc., St. Charles, MO). The limit of sensitivity was 0.5 µg/liter, the intraassay coefficient of variation was 8.3%, and the interassay coefficient of variation was 6.2%. Serum GH concentrations were determined using a time-resolved fluoroimmunoassay (Delfia, Wallac, Inc., Turku, Finland), with a GH sensitivity of 0.011 µg/liter and coefficients of variation of 6.3% (0.4 µg/liter), 5.3% (10.2 µg/liter), and 4.2% (43.4 µg/liter). Samples from each subject were assayed at the same time.

For statistical purposes, undetectable hormone values were assigned the limit of sensitivity of the assay. Hormone levels are presented and analyzed as absolute values (mean ± SE) or as the mean GH peak. Areas under the curve were calculated using a trapezoidal method. Differences between groups in GH, leptin, and BMI values were tested by the Mann-Whitney test. Analysis of relations between variables was performed with lineal and logarithmic models. Values of R2 were tested by ANOVA from the regression analysis.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
With the experimental design performed, five groups of subjects were obtained; all them were matched by sex, a highly relevant point when dealing with leptin analysis. The group of nonobese subjects had a BMI of 22.1 ± 0.9 kg/m2, whereas heterozygous patients had an overweight phenotype with a significantly higher BMI of 27.0 ± 1.0 kg/m2 (P = 0.009) with respect to the nonobese group, and nonsignificantly different from that of the group of control-heterozygous with a BMI of 24.7 ± 1.1 kg/m2 (Fig. 1Go). On the other hand, the homozygous group of leptin-deficient patients had a BMI of 54.4 ± 0.2 kg/m2, and the obese subjects comprising the control-homozygous group had a BMI of 50.3 ± 2.0 kg/m2, both being significantly more obese than the nonobese group (P < 0.0001) and significantly more obese (P < 0.0001) than either the heterozygous or control-heterozygous groups. Thus, both leptin-deficient groups were matched in obesity with their respective control group, and both had higher adiposity than nonobese subjects; in addition, homozygous patients and controls had higher BMI than the two heterozygous groups.



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  		Figure 1. Mean ± SE GH, serum leptin, and BMI in five groups of subjects matched by gender and number of individuals. Homo and hetero refer to homozygous and heterozygous leptin gene mutations leading to total or partial leptin deficiency. Statistically significant differences (P < 0.05) in the following comparisons are indicated: *, vs. the nonobese group; {dagger}, vs. heterozygous patients or heterozygous controls; °, vs. their respective control group.

 
When analyzed by serum leptin concentration (Fig. 1Go), the group of heterozygous patients had a mean leptin level of 2.3 ± 0.1 µg/liter, significantly lower (P = 0.01) than that in the nonobese group (5.4 ± 0.9 µg/liter) and lower (P = 0.02) than that in the control-heterozygous group (5.7 ± 1.2 µg/liter). The homozygous group had the expected abnormal low leptin level of 1.0 ± 0.2 µg/liter, which was significantly (P = 0.006) lower than that in the control-homozygous group (35.0 ± 6.6 µg/liter) and significantly lower (P = 0.01) than that in the nonobese group (5.4 ± 0.9 µg/liter) or the heterozygous group (P = 0.003).

The combined administration of GHRH and GHRP-6 elicited in the nonobese subjects a potent GH discharge with a mean peak of 86.8 ± 8.9 µg/liter (Fig. 1Go). On the other hand, the heterozygous group showed a GH secretion after the stimulus of 28.6 ± 4.9 µg/liter, not different from that of the control-heterozygous group (39.9 ± 10.4 µg/liter); levels in both groups were significantly lower than that in the nonobese group (P = 0.0005 and P = 0.009, respectively). GHRH plus GHRP-6 elicited a GH peak of 9.4 ± 3.0 µg/liter in the homozygous leptin-deficient group and 9.3 ± 1.0 µg/liter in the control-homozygous group. These responses were identical and lower than those in the heterozygous (P = 0.03), control-heterozygous (P = 0.02), and nonobese (P = 0.0007) groups.

In the group analysis it appeared that the GH discharge paralleled adiposity (BMI), but was unrelated to leptin values. To ascertain this on an individual basis, a regression analysis was undertaken between these parameters in the 13 control subjects and separately in the 8 leptin-deficient patients (homo- and heterozygous; Fig. 2Go). The GH peak and BMI were highly correlated in both controls (R2 = 0.71; P = 0.008) and leptin-deficient patients (R2 = 0.74; P < 0.01). On the contrary, although in controls the GH peak correlated negatively with leptin values (R2 = 0.59; P = 0.002), the correlation was positive in leptin-deficient subjects (R2 = 0.49; P = 0.052). As expected, leptin and BMI were highly correlated in controls (R2 = 0.90; P < 0.001) and were negatively correlated in leptin-deficient patients (R2 = 0.75; P = 0.005).



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  		Figure 2. Individual scatter analysis of GH peaks against leptin values or BMI and of leptin values against BMI. {circ}, Control subjects; •, heterozygous leptin-deficient patients; {blacktriangleup}, homozygous leptin-deficient patients. {square} and {blacksquare}, Regression curves of control and leptin-deficient patients, respectively.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present work it has been demonstrated that leptin is not the mediator of the inhibition of GH secretion observed in obesity. Taking advantage of the fact that patients with leptin deficiency due to a missense leptin mutation have a morbid obese phenotype and that heterozygous patients show leptin and adiposity levels between those of normal subjects and homozygous patients, subjects matched by sex and adiposity have been classified into five separate groups. In all cases the GH secretion elicited by the potent stimulus GHRH plus GHRP-6 has paralleled the adiposity values and not the leptin values. In addition to this principal observation, the role of leptin in the overall regulation of GH secretion in man would appear to be minor.

There is no doubt that GH intervenes in the regulation of body composition, and that body composition conditions the pattern of GH secretion (5, 13, 28, 29, 30). In states of malnutrition manifesting a severe reduction in adipose mass, as, for example, in active anorexia nervosa or fasting, relevant alterations in the GH-IGF-I axis and enhanced GH levels plus low leptin secretion have been described (9, 10, 31). At the other extreme, states of lipoaccumulation, such as obesity, are associated with a decrease in the spontaneous and stimulated secretion of GH plus increased leptin levels (5, 15). It is likely that the altered GH secretion develops as a consequence of obesity, as the recovery of spontaneous GH secretion after intense weight loss points to an acquired transient defect (17). Furthermore, from the experimental results in rats, no clear mechanistic explanation appears for the deranged GH secretion, but adiposity seems to be the primary event (12). In addition to the reduction in spontaneous GH secretion, obese patients present a characteristic impaired GH secretion when subjected to all stimuli tested to date, namely hypoglycemia, L-dopa, arginine, glucagon, exercise, opioid peptides, clonidine, and GHRH, and in the deep sleep nocturnal phase (2). Although a reduction in the GH half-life by an enhanced clearance has been clearly demonstrated (13, 32), it is undisputed that the main mechanism altered in obesity is a reduced somatotroph responsiveness to stimuli. Administration of exogenous GHRH (17), drugs aimed at reducing endogenous somatostatinergic tone (33), or drugs that reduce FFA levels (34, 35) enhance, but do not normalize, GH secretion in obese subjects. Although the GH-stimulating hormone ghrelin is decreased in obesity (36), the reduction is too minor to explain the GH changes in obesity. These results were taken as evidence that all of these altered factors contribute to but are not the basic altered mechanisms in obesity. Although highly controversial, IGF-I levels seem to be within the normal range in most studies of obesity (37), making it unlikely that this inhibitory signal is responsible for the reduced GH discharge. Despite the complexity of this disease state, one clear point is that the GH reduction in obesity is not a permanent state, but a functional one, i.e. it may be partially reversible without changes in body weight. In fact, administration of the potent GH stimulus GHRH plus GHRP-6, which operates at both hypothalamic and pituitary levels, is able to partially restore GH secretion in nonmorbid obesity (38).

The common forms of obesity in humans are associated with high levels of circulating leptin and probably with reduced leptin transport through the blood-brain barrier and/or reduced action at hypothalamic receptor level (39). As leptin has been shown to be an important mediator of the functioning of the somatotroph axis (22, 23, 24), a logical deduction was that leptin may well be the signal to the human hypothalamus through which excess adipose mass inhibits GH secretion (5, 40, 41). This working hypothesis is coherent with the reports published on leptin values and GH secretion in some disease states and experimental models (42, 43, 44, 45) and with stepwise regression analysis indicating that leptin has a significant negative effect on GH secretion (28). However, this working hypothesis has not been rigorously addressed until now, as in humans it is not possible to dissociate obesity from leptin levels, which in obesity are severely elevated and correlate with both the percentage of body fat and the BMI (19). Furthermore, changes in somatotrope activity normally precede the variations in leptin levels (44, 45, 46).

In the present work we have studied the stimulated GH secretion in patients with human leptin deficiency and morbid obesity due to a missense mutation in the leptin gene. Contrary to common forms of obesity, these patients present the unique situation of morbid obesity associated with negligible levels of leptin (25, 26). To assess the somatotroph secretory capability the combination of GHRH and GHRP-6 was used, which is one of the most powerful and efficacious stimulants of GH secretion (27). The results unambiguously showed that independently of leptin levels in the circulation, subjects responded to the GH stimulus in a negative correlation with the degree of adiposity, i.e. the more adipose tissue, the less GH released. Patients with partial or total leptin deficiency showed a degree of GH discharge that was exclusively conditioned by the BMI, thus challenging the working hypothesis that leptin was the mediator of the inhibitory influence exerted by adipose tissue on GH secretion (41, 47). Although in leptin-deficient homozygous patients a blockade in GH secretion after insulin tolerance testing has been previously communicated, with GH peaks ranging from 0.07–0.1 µg/liter (25), it should be noted that excess adiposity led to a blockade of insulin tolerance test-mediated GH secretion in otherwise normal subjects (48). One interesting observation of the present work was that three obese subjects, one control with a BMI of 49 kg/m2 and two homozygous leptin-deficient patients, both with BMIs of 54 kg/m2, showed GH peaks under the limit for being considered GH deficient with the GHRH plus GHRP-6 tests (7.3, 6.4, and 6.2 µg/liter, respectively) (27). This implies that in morbid obesity with BMI over 40 kg/m2, the cut-off limits of the GHRH plus GHRP-6 test should be readjusted appropriately.

The present observation indicating that leptin is not the mediator of the GH blockade observed in obesity is not contradictory with the fact that low leptin levels lead to reduced GH pulsatility in rats, perhaps suggesting that the role of leptin in GH regulation is more a permissive than a triggering one. In any case, there are still two unresolved points. 1) What is the signal or the mechanism that in obesity condition the GH blockade? 2) Why have massively obese subjects with or without leptin deficiency, such as these presented in this work, grown normally despite the fact that biochemically they must be defined as GH-deficient subjects? The observation that obese children with no evident or severely reduced GH secretion grow normally is well documented and has been explained by elevated free IGF-I levels or by postulating that basal GH levels in obesity were enough to lead to a normal height. The final explanation for these questions needs further analysis, and perhaps more accurate methods for measuring free IGF-I may clarify these points in the near future.

In conclusion, morbidly obese patients with or without leptin deficiency had GH secretion that was related to adiposity and not to leptin levels. The inhibitory effect of obesity on GH secretion does not seem to be mediated by leptin.


   Acknowledgments
 
The technical collaboration of Ms. Mary Lage is gratefully acknowledged. The expert statistical advice of Prof. X. L. Otero Cepeda (Department of Statistics, University of Santiago de Compostela, Santiago de Compostela, Spain) is acknowledged.


   Footnotes
 
This work was supported by research grants from Fondo de Investigacion Sanitaria, Spanish Ministry of Health; Secretaria Xeral de Investigacion e Desenvolvemento, Conselleria de Educacion Xunta de Galicia; and Direccion General Investigacion Cientifica y Tecnología.

Abbreviations: BMI, Body mass index; FFA, free fatty acids; GHRP-6, GH-releasing peptide-6.

Received January 29, 2002.

Accepted September 30, 2002.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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