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Leptin, Cortisol, and GH Secretion Interactions in Short Normal Prepubertal Children

Department of Pediatrics, University of Parma, 43100 Parma, Italy; and Evgenidion Hospital, Athens University Medical School (G.M.), 11528 Athens, Greece

Address all correspondence and requests for reprints to: Lucia Ghizzoni, M.D., Department of Pediatrics, University of Parma, Via Gramsci 14, 43100 Parma, Italy. E-mail: lucia.ghizzoni{at}.unipr.it

Abstract

The hormonal regulation of the ob gene and leptin secretion in humans is still unclear. To investigate the interactions among leptin, cortisol, and GH, we analyzed and time-cross-correlated their spontaneous 24-h secretion in 12 short normal prepubertal children of both sexes (6 females and 6 males). Time-cross-correlation analyses demonstrated that leptin and cortisol were correlated in both a negative and positive fashion. The negative correlation, with cortisol leading leptin by 4 and 3 h for boys and girls, respectively, might reflect the stimulatory effect of CRH on the sympathetic system, which inhibits leptin secretion; the positive correlation, with leptin leading cortisol by 6 and 5 h for boys and girls, respectively, might reflect a direct effect of leptin on CRH secretion in the hypophyseal portal system. Time-cross-correlation analyses also showed a strong positive correlation between GH and leptin concentrations, with GH leading leptin by 5 and 2 h for boys and girls, respectively, suggesting a possible direct leptin-releasing effect of GH on adipocytes. We conclude that cross-correlation analyses of 24-h hormone secretions under baseline physiological conditions suggest that the hypothalamic-pituitary-adrenal axis might have a prevailing inhibitory effect on leptin secretion, whereas leptin might exert a positive effect on the hypothalamic-pituitary-adrenal axis. The relation between GH and leptin could be a direct one and characterized prevalently by a positive effect of GH on leptin secretion. Further investigations using different experimental systems are needed to ascertain the validity of these mathematically educed conclusions.

LEPTIN, THE PRODUCT of the ob gene, is secreted by adipocytes and regulates food intake and energy expenditure. In rodents and humans, leptin secretion is under hormonal and neural control (1, 2, 3, 4). Synthetic glucocorticoids increase ob mRNA and leptin production in vivo (5, 6), and in vitro (7, 8), whereas chronic administration of leptin to ob/ob mice results in decreased plasma corticosterone levels (9). In addition, leptin inhibits CRH release from the hypothalamus in vitro and blunts plasma ACTH and cortisol responses to restraint stress in vivo (10). Moreover, there is an inverse relation of circadian fluctuations between plasma levels of leptin and those of cortisol and ACTH (11).

Alterations in nutritional status, such as obesity or food deprivation, markedly influence GH secretion. Levels of GH in the pituitary and of GHRH in the hypothalamus were decreased in young db/db mice, and both ob/ob and db/db mice show stunted growth curves (12). Intracerebroventricular administration of leptin antiserum in rodents decreased spontaneous GH secretion, indicating a positive effect of leptin on the growth axis (13). A homozygous mutation in the human leptin receptor gene resulted in early-onset morbid obesity, absence of pubertal development, and reduced GH secretion (14). Obesity in children is characterized by increased linear growth rate in the presence of impaired GH secretion (15). In obese subjects immunoreactive leptin levels were elevated in direct proportion to body fat (8). Conversely, in anorexia nervosa blood GH levels were elevated, whereas serum leptin concentrations were extremely low (16). As GH secretion normalizes after weight loss in obesity or after refeeding in states of food deprivation (15), it is conceivable that altered GH secretion might develop as a consequence of altered metabolic status. The mechanisms by which metabolic status regulate GH secretion or vice versa are not yet understood.

To investigate the interactions among leptin, cortisol, and GH secretion under physiological conditions, we evaluated and time-cross-correlated the 24-h spontaneous secretory patterns in short normal prepubertal children of both sexes.

Subjects and Methods

Subjects

This study was approved by the clinical research committee of the Department of Pediatrics, University of Parma (Parma, Italy). Twelve prepubertal children (six males and six females) with idiopathic short stature, normal GH responses to at least one pharmacological stimulation test (peak GH >10 ng/ml after arginine or clonidine administration), normal 24-h integrated GH concentrations, and IGF-I and IGF-binding protein-3 plasma concentrations were studied. When an abnormal GH response to the first stimulation was obtained, a second test was performed to rule out the presence of GH deficiency. Informed consent was obtained from the children’s parents. The clinical characteristics of the children studied are summarized in Table 1.

At 1000 h, after an overnight fast, an indwelling nonthrombogenic catheter was inserted into an antecubital vein and connected to a portable constant withdrawal pump, according to the method of Kowarski et al. (17). The rate of withdrawal was 4 ml/h, and blood collection tubes were changed every 30 min for 24 h. During this time, children were encouraged to continue normal activity and were given a standard hospital diet. We arbitrarily chose the period from 2200 h in the evening to 1000 h in the morning because we expected the main circadian peaks of leptin, cortisol, and GH to occur during this period. We started the pulsatility study at 1000 h to avoid dividing the morning cortisol surge.

Blood samples for measurements of leptin, cortisol, and GH concentrations were kept at room temperature and centrifuged within 24 h (every 2–4 h during the day and up to 8 h at night). After centrifugation, serum was stored at -20 C until assayed. To validate the collection procedure, we measured leptin concentrations in blood samples centrifuged and stored immediately and 1, 2, 4, 8, 12, and 24 h after their collection. The coefficient of variation between the results obtained from the different samples was less than 8%.

Bone age was determined by the method of Greulich and Pyle (18). Body mass index SD scores were computed based on French percentiles (19).

Hormone assays

Commercial kits were used for the measurement of serum cortisol (RIA, Radim, Pomezia, Italy), GH (immunoradiometric assay, Nichols Institute Diagnostics, San Juan Capistrano, CA), leptin (RIA, Linco Research, Inc., St. Charles, MO), and IGF-I (RIA, Nichols Institute Diagnostics) concentrations. The sensitivities of the assays were 2.48 nmol/liter for cortisol, 0.02 µg/liter for GH, 0.03 nmol/liter for leptin, and 1.76 nmol/liter for IGF-I. Mean intra- and interassay coefficients of variation were, respectively, 4.1% and 6.5% for cortisol, 3.3% and 5.1% for GH, 2.5% and 4.4% for leptin, and 2.7% and 6.8% for IGF-I.

Statistical analysis

Values are reported as the mean ± SEM unless otherwise stated. A test for normality was performed on all data. Statistical significance was determined by the Wilcoxon signed rank test or the Wilcoxon rank sum test, as appropriate. Linear association between two variables was analyzed by linear regression analysis before and after log transformation of the data. The latter was performed to normalize the distribution of the data. P < 0.05 was considered significant.

Time series analyses

To search for a time-ordered relation between leptin and cortisol and between leptin and GH we staggered and correlated the arithmetic (raw data), exponentially transformed (smoothed), and detrended values of the concentration-time series of leptin with those of cortisol and GH, as previously described (20, 21). Cross-correlation analysis between leptin and cortisol and between leptin and GH was computed at 30-min time lags, covering the 24-h study period. If the release of hormone B is regulated by hormone A (A, releasing hormone; B, effector hormone), then one might expect the concentration-time series of hormone B to lag (follow) in time quantitatively the concentration-time series of hormone A. Cross-correlation was computed after lagging (shifting) the concentration-time series of cortisol and GH relative to the concentration time-series of leptin. If we call r_k the coefficient of correlation between cortisol or GH and leptin at a lag time k for one child, then the mean r_k for all children in each group was considered significant when it exceeded zero by more than 2 SE. The SE was calculated from the individual values of r_k for all children at lag time k. All analyses were performed separately for boys and girls because of the known difference in leptin values between sexes.

The simple exponential transformation was used for smoothing the time series values. In this type of transformation, each point is computed as a weighted average of all preceding observations, where greater weight is assigned to more recent observations. The general purpose of the smoothing technique is to reveal the major patterns or trends in a time series while deemphasizing minor fluctuations (random noise).

As circadian periodicity in cortisol or GH and leptin series might result in a significant correlation between them, reflecting only the relative phase of the two circadian rhythms, the trend-subtract technique of transformation was used to eliminate the circadian component. All of these mathematical analyses were performed with the Statistica software for the Windows operating system (22).

Results

Analyses of cortisol and leptin 24-h time series in prepubertal boys (Fig. 1)

Cross-correlation analysis of the raw values. The raw values of the 24-h serum cortisol and leptin concentrations of the male group are shown superimposed in Fig. 1A. The graphs depicting the mean coefficient of correlation from the cross-correlation analyses over the 24 h between the cortisol and leptin raw values are shown in Fig. 1B. A strongly significant negative correlation over time was observed between cortisol and leptin concentrations, peaking at lag time 4 h, with cortisol leading leptin by this time interval. In addition, a slightly significant positive correlation was observed over time between cortisol and leptin concentrations, peaking at lag time 18 h, with cortisol leading leptin by this time interval.

View larger version (37K): [in this window] [in a new window]   Figure 1. Twenty-four-hour serum cortisol (gray area) and leptin (black area) concentrations in boys (A) and girls (C). The gray and black areas delineate the lower and upper quartiles for each hormone. The 24-h secretory profiles of the two hormones have been superimposed for better comparison. Collective graphs depicting the cross-correlation analyses of mean coefficients of correlation over the 24-h period between serum cortisol and leptin concentrations in boys (B) and girls (D). The area between the gray lines includes 0 ± 2 SEM calculated from the individual values of r for all children at lag time and indicates the limits of significance (P < 0.05). Arrows indicate the significant correlations.

Cross-correlation analysis of the smoothed and detrended values. The cross-correlation of the smoothed and detrended leptin and cortisol values did not reveal any major difference compared with that of the raw values (data not shown).

Analyses of cortisol and leptin 24-h time series in prepubertal girls (Fig. 1)

Cross-correlation analysis of the raw values. The raw values of the 24-h serum cortisol and leptin concentrations of the female group are shown superimposed in Fig. 1C. The graphs depicting the mean coefficient of correlation from the cross-correlation analyses over the 24 h between the cortisol and leptin raw values are shown in Fig. 1D. A strongly significant negative correlation over time was observed between cortisol and leptin concentrations, peaking at lag time 3 h, with cortisol leading leptin by this time interval. In addition, there was a slightly significant positive correlation over time between cortisol and leptin concentrations, peaking at lag time 13.5 h, with cortisol leading leptin by these time intervals.

A strongly significant positive correlation was observed over time between leptin and cortisol levels, peaking at lag time -5 h, with leptin leading cortisol by this time interval. In addition, a significant negative correlation was detected over time between leptin and cortisol concentrations, peaking at lag time -18.5 h, with leptin leading cortisol by this time interval.

Cross-correlation analysis of the smoothed and detrended values. The cross-correlation of the smoothed and detrended leptin and cortisol values did not reveal any major difference compared with that of the raw values (data not shown).

Analyses of GH and leptin 24-h time series in prepubertal boys (Fig. 2)

Cross-correlation analysis of the raw values. The raw values of the 24-h serum GH and leptin concentrations of the male group are shown superimposed in Fig. 2A. The graphs depicting the mean coefficient of correlation from the cross-correlation analyses over the 24 h between the GH and leptin raw values is shown in Fig. 2B. A strongly significant positive correlation over time was observed between GH and leptin concentrations, peaking at lag time 5 h, with GH leading leptin by this time interval. In addition, a slightly significant negative correlation was observed over time between GH and leptin concentrations, peaking at lag time 16.5 h, with GH leading leptin by this time interval.

View larger version (38K): [in this window] [in a new window]   Figure 2. Twenty-four-hour serum GH (gray area) and leptin (black area) concentrations in boys (A) and girls (C). The gray and black areas delineate the lower and upper quartiles for each hormone. The 24-h secretory profiles of the two hormones have been superimposed for better comparison. Collective graphs depicting the cross-correlation analyses of mean coefficients of correlation over the 24-h period between serum GH and leptin concentrations in boys (B) and girls (D). The area between the gray lines includes 0 ± 2 SEM calculated from the individual values of r for all children at lag time and indicates the limits of significance (P < 0.05). Arrows indicate the significant correlations.

Cross-correlation analysis of the smoothed and detrended values. The cross-correlation of the smoothed and detrended GH and leptin values did not reveal any major difference compared with that of the raw values (data not shown).

Analyses of GH and leptin 24-h time series in prepubertal girls (Fig. 2)

Cross-correlation analysis of the raw values. The raw values of the 24-h serum GH and leptin concentrations of the female group are shown superimposed in Fig. 2C. The graph depicting the mean coefficient of correlation from the cross-correlation analysis over the 24 h between the GH and leptin raw values is shown in Fig. 2D. A strongly significant positive correlation over time was observed between GH and leptin concentrations, peaking at lag time 2 h, with GH leading leptin by this time interval. In addition, a slightly significant negative correlation was observed over time between GH and leptin concentrations, peaking at lag time 11.5 h, with GH leading leptin by these time intervals.

A significant negative correlation was observed over time between leptin and GH levels, peaking at lag time -8.5 h, with leptin leading GH by these time intervals. In addition, a slightly significant positive correlation was detected over time between leptin and GH concentrations, peaking at lag time -19 h, with leptin leading GH by this time interval.

Cross-correlation analysis of the smoothed and detrended values. The cross-correlation of the smoothed and detrended leptin and GH values did not reveal any major difference compared with that of the raw values (data not shown).

Linear regression analysis of serum IGF-I hormone concentrations and leptin secretory parameters

The relationships between daytime, nighttime, and 24-h parameters of leptin secretion as defined by the Pulsar program (23) and baseline morning serum IGF-I concentrations were evaluated using linear regression analysis. No significant relation was found between IGF-I serum concentrations and daytime, nighttime, or 24-h mean leptin levels, mean area under the curve above baseline, area under the curve above zero, peak characteristics (height, amplitude, area, and length), interpeak interval, and number of leptin peaks.

Discussion

The results of the present study demonstrate that cortisol and leptin are related to each other in a time-related negative and positive fashion, as mathematically proven by cross-correlation analysis that showed the highest negative correlation when cortisol values preceded leptin values by 4 and 3 h in boys and girls, respectively, with cortisol leading leptin. This reciprocal relation might reflect the stimulatory effect of CRH on the sympathetic system (24), which would lead to peripheral norepinephrine release and inhibition of leptin secretion via ß₃-adrenergic receptors (3, 25). Such a mechanism might explain the initial decrease in leptin levels that follows a cortisol surge during the acute perioperative stress response (26).

Interestingly, there was also a positive correlation between cortisol and leptin at lag times of 6 and 5 h for boys and girls, respectively, with leptin leading cortisol. This means that in both female and male subjects, a rise of leptin precedes a rise of cortisol levels by 6 and 5 h, respectively. This might be explained by a direct stimulatory effect of leptin on CRH by sympathotropic neurons of the paraventricular nucleus (27). Intracerebroventricular injection of leptin in rats, in fact, increases CRH mRNA levels in the paraventricular nucleus (28).

There was a strong positive correlation between leptin and GH concentrations at lag times of 5 and 2 h for boys and girls, respectively, with GH leading leptin, meaning that a rise of GH was followed by a rise of leptin levels. This finding, extracted mathematically by cross-correlation analyses, suggests a possible direct leptin-releasing effect of GH on adipocytes. In vitro studies showed a direct effect of GH on leptin gene expression in the liver and adipose tissue of domestic birds (29) and an up-regulation of leptin receptor gene expression in the anterior pituitary gland of human GHRH transgenic mice (30). A leptin-stimulating action of acute GH administration was recently described in elderly subjects with GH deficiency (31). This increase was independent of insulin and IGF-I, suggesting a direct effect of GH. In the present study no significant relation was found between IGF-I serum concentrations and any of the daytime, nighttime, and 24 h leptin secretory parameters, suggesting either that the effect of one hormone on the other is too rapid to alter IGF-I abundance or the existence of a direct relation between leptin and GH. An acute rise in leptin concentrations after reactivation of the GH-IGF axis by GH segretagogues was also reported in critically ill patients (32). Whether these findings reflect a role for GH in the physiological regulation of leptin secretion remains to be determined. There was also a significant negative correlation over time between leptin and GH levels, peaking at lag times -11 and -8.5 h for boys and girls, respectively, with leptin leading GH by these time intervals, meaning that a rise of leptin precedes a nadir concentration of GH. This is in agreement with other reports indicating that leptin and GH are inversely correlated in both GH-deficient patients (33, 34) and postmenopausal normal women (35). In normal children a negative correlation between leptin and 24-h GH secretion was recently described (36). The mechanism by which leptin levels are inversely correlated to GH secretion has not been established. Leptin may inhibit GH secretion by a direct effect on either the pituitary or the hypothalamus or by stimulating somatostatin secretion. The data available to date, however, seem to indicate a suppressive effect of leptin on somatostatin (37) and vice versa (38). On the other hand, it cannot be ruled out that this negative correlation between leptin and GH might be merely the mathematically revealed mirror image of the strong positive correlation between GH and leptin.

We conclude that cross-correlation analyses of 24-h hormone secretions under baseline physiological conditions suggest that the hypothalamic-pituitary-adrenal axis might have a prevailing inhibitory effect on leptin secretion, whereas leptin might exert a positive effect on the hypothalamic-pituitary-adrenal axis. The relation between GH and leptin could be a direct one and characterized prevalently by a positive effect of GH on leptin secretion. Further investigations in different experimental systems are needed to ascertain the validity of these mathematically deduced conclusions.

Footnotes

This work was presented in part at the 37th ESPE Meeting, Florence, Italy, September 24–27, 1998 (Abstract P-113).

Received October 10, 2000.

Accepted April 23, 2001.

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