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Division of Neuroscience (H.F.U.) and Division of Reproductive Sciences (K.-Y.F.P.), Oregon Regional Primate Research Center, Beaverton, Oregon 97006; and Department of Physiology and Pharmacology (H.F.U.), Oregon Health Sciences University, Portland, Oregon 97201
Address all correspondence and requests for reprints to: Henryk F. Urbanski, Division of Neuroscience, Oregon Regional Primate Research Center, 505 Northwest 185th Avenue, Beaverton, Oregon 97006. E-mail: urbanski{at}ohsu.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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1 kg/yr during
the first decade of life and reached a plateau at approximately 13 yr.
In contrast, serum leptin concentrations showed a biphasic
developmental pattern, which was highlighted by a strong negative
correlation with body weight (r = -0.74, P <
0.001) before the onset of puberty (at 3.5 yr) and by a strong
positive correlation afterward (r = 0.77, P <
0.001). Overall, the developmental changes in serum leptin
concentrations closely mimicked the expected developmental changes in
serum testosterone concentrations (r = 0.62, P
< 0.001), which were highly elevated at birth, fell to basal levels
during the juvenile phase of development, and gradually rose again
after the initiation of puberty. However, mean serum leptin
concentrations during the peripubertal period itself (3–5 yr) were
significantly lower (P < 0.01) than those observed
during the first year of life or those observed in fully mature adults
(i.e. >7 yr) (3.5 ± 0.3, 1.4 ± 0.2, and
3.3 ± 0.6 ng/ml, respectively). These data demonstrate that the
role of leptin in energy homeostasis of primates is more than a simple
linear relationship, being highly dependent upon the developmental age.
Furthermore, the data do not support the hypothesis that leptin plays a
major role in triggering the onset of puberty in primates, although the
strong correlation between serum concentrations of leptin and
testosterone suggests that the secretion of these two hormones may be
causally linked. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hormone assays
All of the blood samples were collected in the morning, and the
serum was stored frozen. Leptin was measured using a primate leptin RIA
kit (Linco Research, Inc., St. Charles, MO); this uses a rabbit
antiprimate leptin antibody and recombinant human leptin for the
standards and tracer. The minimum detectable concentration at 95%
binding was 0.7 ng/ml, and the intraassay coefficient of variation was
6%; all of the serum samples were assayed together in a single RIA.
Serum testosterone was measured by RIA as previously described
(11).
Statistics
Pearson’s correlation was used to analyze the relationship
between the serum concentration of leptin and body weight and the serum
concentrations of leptin and testosterone. Differences between mean
hormone concentrations were analyzed by ANOVA followed by the
Newman-Keuls test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 kg/yr) well into the
second decade of life (Fig. 1
, upper panel), whereas serum concentrations of testosterone
showed the characteristic triphasic primate developmental pattern (Fig. 1, middle panel); testosterone concentrations were elevated
at birth, fell sharply during the latter half of the first year, and
then remained at basal levels until the initiation of puberty, at
3.5 yr. The developmental pattern of serum leptin concentrations was
essentially similar to that of testosterone, being highlighted by a
steady decrease from birth until the onset of puberty and then by a
steady increase starting at 5–6 yr (Fig. 1, lower
panel). Although mean serum leptin concentrations appeared to show
a transitory peak during the peripubertal period (3–5 yr), this was
not significant. Moreover, mean (± SEM) serum leptin
concentrations at this time were significantly lower (P
< 0.01) than those observed in the very young animals (<1 yr) or in
the fully mature adults (>7 yr) (i.e. 3.5 ± 0.3,
1.4 ± 0.2, and 3.3 ± 0.6 ng/ml, respectively). Overall, the
concentration of serum leptin showed a significant correlation with
that of serum testosterone (r = 0.62, P < 0.001),
even in the adults (Fig. 2). In contrast,
the relationship between the concentration of serum leptin and body
weight was clearly biphasic (Fig. 3). In
the prepubertal animals, which had a body weight of <5 kg, the
correlation was strongly negative (r = -0.74, P
< 0.001) whereas in adults the correlation was strongly positive
(r = 0.77, P < 0.001).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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6 ng/ml, respectively). Similar concentrations (7.2
ng/ml) have also been observed in some obese adult males, whereas in
others the concentrations were markedly higher (35.3 ng/ml) (13).
Although the oldest animals used in the present study were clearly not
obese, the high variability in their serum leptin concentrations most
likely stems from individual variation in body fat content. The novel aspect of the present study, however, is that circulating leptin concentrations were examined across the entire postnatal phase of development (i.e. from the day of birth well into adult life). Consequently, it has been possible to disclose that the developmental changes in serum leptin closely mimic the well established developmental changes in serum testosterone (14). In both cases, the circulating concentrations of these hormones were found to be highly elevated at birth. Serum testosterone concentrations then declined sharply toward the end of the first year followed by a more gradual decline in serum leptin concentrations. By the time the animals become juveniles, both serum testosterone and leptin concentrations reached a nadir and both subsequently rose again during the transition to adulthood.
Recent studies in boys have demonstrated that the onset of puberty is
associated with a transitory increase in circulating leptin
concentrations (6), suggesting that leptin might play an important role
in triggering the development of the reproductive axis. On the other
hand, it has also been reported that an increase in circulating leptin
concentrations does not occur in male rhesus macaques from 26 weeks
before, to 9 weeks after, the pubertal increase in testosterone
secretion (10). The present results are in agreement with the latter
observation, in that no obvious peak in serum leptin concentrations was
detected in male rhesus monkeys during the peripubertal period
(i.e. 3.5–5 yr). Indeed, serum leptin concentrations at
this time were significantly (P < 0.01) lower than
those observed in the very young animals (<1 year) and also in the
fully mature adults. Although it is possible that a significant
peripubertal peak in serum leptin concentrations was missed because of
an inadequate group size at critical time points (i.e. a
limitation of the cross-sectional design of the study), the data
clearly suggest that a major increase in serum leptin concentrations
does not occur until well after the testes have started their pubertal
growth (3.5 yr) and after the daytime serum concentrations of
testosterone have already begun to increase. Taken together, the data
from male rhesus macaques do not support the hypothesis that leptin
plays a critical role in the onset of primate puberty, although it is
plausible that leptin plays a permissive role, as has been suggested
for the female rat (7).
A significant finding from the present results is that body weight showed a steady increase throughout the first decade of life, but in marked contrast, serum concentrations of leptin showed a biphasic developmental pattern. These concentrations were elevated both in the neonatal/infantile animals as well as in the adults, although not as highly as has previously been observed in some obese adult animals (13). The strong negative correlation between serum leptin concentrations and body weight before puberty makes physiological sense, particularly during the peripubertal period when the attainment of a critical body weight is important for maturation of the reproductive axis. The strong positive correlation between serum leptin concentrations and body weight after puberty is likely to reflect a more stable homeostatic relationship between adipocytes and the appetite control centers of the central nervous system.
The source of the prepubertal leptin, especially during the first year of life, remains to be elucidated. However, it has recently been shown in hamsters that both white and brown adipose tissue contains messenger RNA (mRNA) coding for leptin (15). Therefore, although brown adipose tissue is generally associated with thermogenesis rather than energy storage (16), it is plausible that the brown adipose tissue observed in primates during early postnatal development (17) contributes significantly to the circulating concentrations of leptin before puberty.
The strong positive correlation between circulating concentrations of leptin and testosterone that occurred throughout postnatal development begs the question of whether the secretion of these two hormones is causally related. In rhesus macaques, the pubertal increase in serum testosterone concentrations does not appear to be preceded by a significant increase in serum leptin concentrations (10). Therefore, it is unlikely that leptin plays a direct role in modulating the secretion of gonadal steroids. On the other hand, it is plausible that gonadal steroids exert some influence on the secretion of leptin. Although this hypothesis has not been tested specifically it is interesting that the developmental changes in serum leptin concentrations were apparently preceded by changes in testosterone (this study). In addition, the low circulating leptin concentrations of peripubertal male rhesus macaques appeared to be even lower in animals that had previously been orchidectomized (10).
Taken together, these data emphasize that the physiological role of leptin in regulating body weight and sexual maturation in primates is more complicated than previously demonstrated and that the relationship between circulating leptin concentrations and body weight changes radically as animals make the transition from the prepubertal to postpubertal phase of somatic maturation.
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Footnotes |
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Received December 22, 1997.
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