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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 5 2065-2072
Copyright © 2001 by The Endocrine Society

Original Studies

Interactions of Leptin and Thyrotropin 24-Hour Secretory Profiles in Short Normal Children

Lucia Ghizzoni, George Mastorakos, Mariangela Ziveri, Mariangela Furlini, Angela Solazzi, Alessandra Vottero and Sergio Bernasconi

Department of Pediatrics, University of Parma (L.G., M.Z., M.F., A.S., A.V., S.B.), 43100 Parma; 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: lughizzo{at}unipr.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Thyroid hormones and leptin have effects on similar aspects of body homeostasis, such as energy expenditure, thermogenesis, and metabolic efficiency. Thus, the cross-talk between the thyrostat and the lipostat might play a crucial role in the maintenance of body homeostasis. To investigate the relationship between the hypothalamic-pituitary-thyroid (HPT) axis and leptin under physiological conditions, we evaluated the pulsatility and circadian rhythmicity and time-cross-correlated the 24-h secretory patterns of leptin and TSH in 12 short normal prepubertal children (6 girls and 6 boys). In both male and female subjects, leptin was secreted in a pulsatile and circadian fashion, with a nocturnal leptin surge that was more pronounced in males than in females. Mean 24-h leptin levels and total area under the curve were significantly higher in girls than in boys. This was mainly due to the nighttime mean leptin levels and total area under the curve, which were higher than those in boys. The cross-correlated 24-h leptin and TSH levels revealed significant positive and negative correlations. The positive one, of leptin over TSH, suggests a positive feedback regulation by leptin on the HPT axis, which might play an important role in triggering the neuroendocrine response to starvation, including decreased thyroid hormone levels. The negative correlation, of TSH over leptin, could explain the compensatory changes in adipocyte metabolism, and indirectly in circulating leptin levels, in response to alterations in thyroid status. In conclusion, we suggest that under baseline physiological conditions, the HPT axis has a prevailing inhibitory effect on leptin secretion, whereas leptin has a prevailing positive effect on the HPT axis. The sexual dimorphism in leptin levels does not seem to influence in a major way the interactions between the HPT axis and leptin.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
LEPTIN, THE PRODUCT of the ob gene, is a hormone secreted by adipocytes that regulates food intake and energy expenditure. In rodents, leptin expression appears to be under hormonal control (1, 2, 3), but its regulation and metabolism in humans are still poorly understood. Serum leptin levels show a strong positive correlation with body fat. They are elevated in obesity (4) and decreased in states of severe malnutrition, such as anorexia nervosa (5). On the other hand, alterations of the hypothalamic-pituitary-thyroid (HPT) axis are associated with energy and body weight changes. As both thyroid hormones and leptin have effects on similar aspects of body homeostasis, the cross-talk between the thyrostat and the lipostat might play a crucial role in the maintenance of the body homeostasis.

Thyroid hormones were shown in vitro to increase leptin messenger ribonucleic acid (mRNA) expression and secretion in fully differentiated adipocytes (6). Thyroidectomized rats infused with either placebo or high doses of thyroid hormones causing hyperthyroidism showed elevated and suppressed leptin levels, respectively, compared with intact animals infused with placebo (7). In another study, hypothyroid rats showed elevated leptin mRNA levels that normalized after appropriate thyroid hormone treatment (8). Thus, it seems that there is a discrepancy between the in vitro and in vivo animal data. Human data also show inconsistent results. In some studies hypothyroid patients showed low leptin levels compared with matched controls (9, 10). In other studies no difference was found in leptin levels between normal subjects and hypothyroid patients (11, 12, 13). On the other hand, there are also reports of increased leptin levels in hypothyroid patients (14, 15). Most of the clinical studies have found no effect of hyperthyroidism on leptin levels (9, 13, 16), although two reports suggest relative hypoleptinemia (14, 17), and one found a small increase in leptin levels in thyrotoxicosis (18).

Prolonged fasting, starvation, and weight loss are associated with low serum T3 and T4 levels and, paradoxically, low or normal TSH levels. In rats, fasting results in low pituitary TSH content and decreased expression of TRH in hypophyseal portal blood (19, 20). Leptin administration to fasting animals restores most of these changes, including normalization of circulating thyroid hormone levels, and prevents suppression of pro-TRH mRNA levels (21, 22). Recently, patients with a mutation in the leptin receptor gene were reported to be hypothyroid, with low levels of free T4, normal levels of TSH, and a delayed response of TSH to TRH stimulation, indicating hypothalamic hypothyroidism (23). The same hormonal alteration was described in children with leptin deficiency (24), whereas in adult patients thyroid function tests were normal (25).

To investigate the interactions between leptin and HPT under physiological conditions in both genders, we evaluated and time-cross-correlated the 24-h spontaneous secretory profiles of leptin and TSH in short normal prepubertal boys and girls.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

This study was approved by the clinical research committee of the Department of Pediatrics at the University of Parma (Parma, Italy), and informed consent was obtained from the children’s parents. For ethical reasons a 24-h pulsatility study could not be performed in normal children; therefore, 12 prepubertal children (6 males and 6 females) with familial short stature and normal hypothalamic-pituitary function were selected for the study. All subjects were clinically and biologically euthyroid and had normal blood thyroid hormone levels. Their clinical characteristics are summarized in Table 1Go.


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  		Table 1. Clinical profile of children

 
Protocol

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. (26). 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 have normal activity and had a standard hospital diet. Blood samples for measurements of leptin and TSH concentrations were kept at room temperature and centrifuged within 24 h. After centrifugation, serum was stored at -20 C until assayed. Baseline blood samples were also drawn to measure free T4 (FT4) and free T3 (FT3) serum concentrations.

Bone age was determined by the method of Greulich and Pyle (27).

Hormone assays

Commercial kits were used for the measurement of serum TSH (immunoradiometric assay, Nichols, San Juan Capistrano, CA), leptin (RIA, Linco Research, Inc., St. Charles, MO), and FT4 and FT3 (enzyme-linked immunosorbent assay, Roche Molecular Biochemicals, Mannheim, Germany) concentrations. The sensitivities of the assays were 0.04 mU/L for TSH, 0.5 ng/mL for leptin, 1.3 pmol/L for FT4, and 0.46 pmol/L for FT3. Mean intra- and interassay coefficients of variation were, respectively, 4.4% and 6.8% for TSH, 2.5% and 4.4% for leptin, 5.6% and 9% for FT4, and 4.2% and 5% for FT3.

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. The level of significance was set at P < 0.05.

Pulse analysis

The Pulsar program was used to quantitate the pulse properties of leptin time series objectively (28). Samples were analyzed for 24- and 12-h serum hormone concentrations, area under the curve above baseline (AUCb), area under the curve above zero line (AUCo), number of significant pulses, mean pulse height, mean pulse amplitude, mean pulse area, mean pulse length, and mean interpulse interval. The cut-off parameters G1–5 were set at 5, 3, 2, 1.5, and 1 times the intraassay SD as criteria for accepting peaks 1, 2, 3, 4, and 5 points wide, respectively. The smoothing time was set at half the total profile time, that is 12 h (24 points) and 24 h (48 points) for the 12- and 24-h profiles, respectively.

Time series analyses

To search for a time-ordered relation between leptin and TSH we staggered and correlated the arithmetic (raw data), exponentially transformed (smoothed), and detrended values of the concentration-time series of leptin with those of TSH. Cross-correlation analysis between leptin and TSH was computed at 30 min time lags covering the 24-h study period, as previously described (29, 30). 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).

The trend subtract technique of transformation was used for detrending the time series values to remove the trend over time that might be related with the circadian rhythm. All of these mathematical analyses were performed with Statistica software for the Windows operating system (31).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Leptin 24-h profile and pulsatility in boys (Fig. 1AGo) and girls (Fig. 1BGo)

Twenty-four-hour, daytime (1000–2200 h), and nighttime (2200–1000 h) mean, mean AUCb, AUCo, peak characteristics (height, amplitude, area, and length), interpeak interval, and number of peak leptin values (±SEM) are reported separately for prepubertal girls and boys in Table 2Go. Twenty-four-hour mean and mean AUCo values were significantly higher in girls than in boys. The remaining 24-h parameters examined were not significantly different between the two groups. In both groups of children mean, mean AUCo, and peak height were higher at night than during the day, but reached statistical significance in boys only. No differences were observed in the daytime secretory parameters of leptin between the two groups. The nighttime mean and mean AUCo values, however, were significantly higher in girls than in boys.



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  		Figure 1. Twenty-four-hour serum leptin (A, boys; B, girls) and TSH (C, boys; D, girls) concentrations. The solid line represents the median of values, the dotted lines represent the minimum and maximum values, and the shaded area delineates the lower and upper quartiles. Such a plot (box plot) was chosen to best show outliers and asymmetric behavior.

 

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  		Table 2. Properties of pulsatile leptin release in prepubertal boys and girls

 
To verify that the differences detected between the leptin secretory parameters in males and females were not due to the specific study period evaluated, analysis of the values obtained in the study period from 1000–2200 h was also performed on the values of the arbitrarily chosen period from 0800–2000 h. The differences observed between the female and male groups during the 0800–2000 h study period were identical to those detected in the 1000–2200 h study period.

Linear regression analysis of serum thyroid hormone concentrations and leptin secretory parameters

The relationships between daytime, nighttime, and 24-h parameters of leptin secretion and serum thyroid hormone concentrations were evaluated using linear regression analysis. A positive relationship was observed between FT4 serum concentration and daytime values of leptin AUCb (r = 0.9; P < 0.05), peak length (r = 0.92; P < 0.05), height (r = 0.94; P < 0.05), and amplitude (r = 0.88; P < 0.05) in females and AUCo (r = 0.99; P < 0.05) and peak height (r = 0.99; P < 0.05) in males (data not shown). There was no correlation between nighttime and 24-h leptin values and FT4 serum levels. No significant relation was found between FT3 serum concentrations and any of the daytime, nighttime, or 24-h leptin secretory parameters.

TSH 24-h profile and pulsatility in boys (Fig. 1CGo) and girls (Fig. 1DGo)

Data on pulsatile TSH secretion analyzed separately in girls and boys were not different in the two groups (data not shown) and were similar to those previously reported (29).

Analyses of leptin and TSH 24-h time series in prepubertal boys

Cross-correlation analysis of the raw values. The mean coefficient of correlation for each time point of the 24-h cross-correlated raw values of the two hormones is depicted in Fig. 2AGo. There was a strongly significant positive correlation over time between leptin and TSH, peaking at a 2-h lag time, with leptin leading TSH. There was also a negative correlation over time, peaking at a 15.5-h lag time, with leptin leading TSH. On the other hand, there was one significant negative correlation over time, peaking at a 13-h lag time, with TSH leading leptin.



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  		Figure 2. Collective graphs depicting the cross-correlation analyses of mean coefficients of correlation over the 24-h period between serum leptin and TSH raw (A) and smoothed (B) concentrations in prepubertal boys. The area between the dotted lines includes 0 ± 2 SEM calculated from the individual values of rk for all children at the lag time k and indicates the limits of significance (P < 0.05).

 
Cross-correlation analysis of the smoothed values. The graph depicting the mean coefficient of correlation for each time point of the cross-correlated smoothed values of the two hormones over 24 h is depicted in Fig. 2BGo. There was a strongly significant positive correlation over time between leptin and TSH, peaking at a 1.5-h lag time, with leptin leading TSH. There was also a negative correlation over time, peaking at a 16-h lag time, with leptin leading TSH. On the other hand, there was only one significant correlation over time, with TSH leading leptin, which was negative and peaked at a 13.5-h lag time.

The cross-correlation of the transformed leptin and TSH values according to the trend subtract transformation technique did not reveal any major difference compared with the raw values (data not shown).

Analyses of leptin and TSH 24-h time series in prepubertal girls

Cross-correlation analysis of the raw values. The mean coefficient of correlation for each time point of the 24-h cross-correlated raw values of the two hormones is depicted in Fig. 3AGo. There was a strongly significant positive correlation over time between leptin and TSH, peaking at a 0-h lag time, with leptin leading TSH. There was also a significant negative correlation over time, with leptin leading TSH, peaking at a 7-h lag time. On the other hand, there was a significant negative correlation, with TSH leading leptin over time, peaking at a 10-h lag time.



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  		Figure 3. Collective graphs depicting the cross-correlation analyses of mean coefficients of correlation over the 24-h period between serum leptin and TSH raw (A) and smoothed (B) concentrations in prepubertal girls. The area between the dotted lines includes 0 ± 2 SEM calculated from the individual values of rk for all children at the lag time k and indicates the limits of significance (P < 0.05).

 
Cross-correlation analysis of the smoothed values. The mean coefficient of correlation for each time point of the 24-h cross-correlated smoothed values of the two hormones is depicted in Fig. 3BGo. There was a significant positive correlation over time between leptin and TSH, peaking at a 0-h lag time. On the other hand, there was only one significant correlation over time, with TSH leading leptin, which was negative and peaked at a 13-h lag time.

The cross-correlation of the transformed leptin and TSH values according to the trend subtract transformation technique did not reveal any major difference compared with the raw values (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of the present study indicate that leptin and the HPT axis are closely related. Correlation analysis demonstrated, in fact, that TSH and leptin correlated to each other over time in both a positive and a negative fashion. A positive relation between the daytime secretory parameters of leptin secretion and FT4 was also observed. When cross-correlation analysis was performed between 24-h TSH and leptin raw and smoothed values, the highest positive correlation was observed when leptin values preceded TSH values, with a lag time of 2–1.5 h for raw and smoothed values, respectively, in boys and of 0 h in girls, with leptin leading TSH. This positive correlation between leptin and TSH might indicate a positive regulation of the HPT axis by leptin through its direct interaction on TRH-synthesizing neurons in the paraventricular nucleus (32, 33) and/or indirectly through the POMC/agouti-related peptide pathway (34). Data from animals subjected to starvation and from ob/ob mice are in favor of this hypothesis. In rats, fasting results in low pituitary TSH content and decreased expression of TRH in hypophyseal portal blood (19, 20). Leptin administration to fasting animals restores most of these changes, including normalization of circulating thyroid hormone levels, and prevents suppression of pro-TRH mRNA levels (21, 22). In the ob/ob mouse, which is in the functional state of starvation at the hypothalamic level, a low circulating level of thyroid hormones is an early abnormality (35, 36). The positive correlation between leptin and TSH can explain the increase in TSH levels frequently observed in patients recovering from the euthyroid sick syndrome (37). The increased leptin levels found in these patients, in fact, may (via the sympathetic nervous system) directly or indirectly increase TRH production and, in turn, TSH levels (38). Decreased thyroid hormone levels, on the other hand, may have a positive feedback effect on leptin levels observed in this patient population (39).

There was also a negative correlation between TSH and leptin raw and smoothed values at lag times of 13–13.5 and 10–13 h for boys and girls, respectively, with TSH leading leptin. This means that in both female and male subjects, a burst of TSH is followed by a nadir in leptin levels at these time intervals and vice versa. An inverse relation between thyroid hormones and leptin was shown in experimental animals over a wide range of thyroid hormone levels, ranging from severe hypothyroidism to hyperthyroidism. Escobar-Morreale et al. reported that hypothyroidism after thyroidectomy in rats led to a significant increase in adipocyte leptin mRNA expression and the leptin/body ratio (7). Replacement with increasing doses of thyroid hormone resulted in a progressive decline in leptin mRNA expression and normalization of this ratio (7, 8). More controversial is the effect of thyroid hormones on leptin secretion in humans, and studies on the effect of thyroid status on leptin levels are discordant (9, 10, 11, 12, 13, 14, 15, 16, 17). In physiological conditions, such as the one we studied, it appears that thyroid status affects leptin levels in a negative fashion. Thyroid hormones have a permissive role on the effects of catecholamines on ß-adrenergic receptors (40). As stimulation of these receptors suppresses leptin expression, thyroid hormones might exert an inhibitory effect on leptin secretion through activation of these receptors.

The negative correlation between leptin and TSH raw value at lag times of 15.5 and 7 h for boys and girls, respectively, could either be the mirror image of the preceding positive correlation, as observed in cross-correlation analyses with significant correlation results, or reflect the temporal difference of the circadian phase of the two hormones.

The results of the present study also showed a difference in serum leptin levels between males and females, as previously reported in children and adults (41, 42, 43, 44). In both female and male subjects there was a nighttime increase in leptin secretion that was more pronounced in males. This was mostly due to an augmentation of the quantitative parameters of the hormone secretion (AUCo and mean values), whereas the pulse characteristics were similar in the two groups. A sexual dimorphism in plasma leptin concentrations at birth and in prepubertal children was previously described (45, 46, 47). However, numerous other studies have not detected significant gender effects on circulating concentrations of leptin normalized to fat mass (48, 49) or body mass index (50) before late puberty. Recently, it was reported that it is the increased production rate of leptin per unit mass of adipose tissue in women together with a higher proportion of adipose tissue that are responsible for the sexual dimorphism in leptin concentrations (51) rather than the anatomical differences of body fat mass (52). Moreover, it has been shown that there is no difference in serum leptin binding activity between prepubertal boys and girls (53). Regarding the leptin receptor isoforms, it has been suggested that estradiol as well as fasting might exert a differential regulatory role on the sensitivity of these receptors in discrete regions of the brains of obese Zucker female rats (54). However, there is no report as yet proving that gonadal steroids have a measurable differential effect on leptin receptors in males and females. In contrast, in vivo and in vitro studies support a primary role of gonadal hormones in determining the sexual dimorphism in serum leptin concentrations. Incubation of adipose tissue with testosterone decreases leptin mRNA expression, and the circulating testosterone concentration accounts for a significant fraction of the variability in circulating concentrations of leptin in obese boys at all stages of puberty (55) and in adult men (56). In vivo administration of estrogen increases circulating levels of leptin in humans and rodents (57), and in vitro leptin production by omental adipose tissue from women, but not men, is increased by estradiol (58). The observation of a sexual dimorphism in circulating leptin concentrations before puberty, on the other hand, suggests that factors other than gonadal steroids may account for some of the gender difference in circulating leptin.

The difference in leptin levels between males and females does not seem to influence the interaction between leptin and the HPT axis, as the results of the cross-correlation analyses were similar in boys and girls. The differences in the correlation lag times detected between males and females might represent a qualitative feature of the sexual dimorphism in leptin secretion.

In summary, our data suggest that leptin and the hypothalamic-pituitary-thyroid axis are closely related. The positive regulatory role of leptin on the HPT axis might be particularly important during starvation. Prolonged fasting has profound inhibitory effects on leptin levels, and falling leptin levels might be a critical sign that could initiate the neuroendocrine response to starvation, which includes decreasing thyroid hormone levels (21). The inverse relation between TSH and leptin, on the other hand, could explain the changes in adipocyte metabolism, and thus of circulating leptin levels, resulting from the alterations in thyroid status. Although the results of the present study are likely to reflect normal physiology, an as yet unknown alteration of hormones in familial short stature might also contribute to the described hormone relationships.

In conclusion, we suggest that under baseline physiological conditions the HPT axis might exert, directly or indirectly, an inhibitory effect on leptin secretion, whereas leptin exerts a positive stimulatory effect on the HPT axis. The sexual dimorphism in leptin levels does not seem to influence the interactions between the HPT axis and leptin.

Received November 11, 1999.

Revised May 18, 2000.

Revised August 8, 2000.

Accepted January 16, 2001.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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