Endocrinology Vol. 142, No. 12 5167-5171
Copyright © 2001 by The Endocrine Society
Direct Modification of Somatotrope Function by Long-Term Leptin Treatment of Primary Cultured Ovine Pituitary Cells
Sang-Gun Roh,
Gui-Ying Nie,
Kylie Loneragan,
Arieh Gertler and
Chen Chen
Prince Henry’s Institute of Medical Research (S.-G.R., G.-Y.N.,
K.L., C.C.), Clayton, Victoria 3168, Australia; Laboratory of Animal
Molecular Physiology, Faculty of Agriculture, Shinshu University
(S.-G.R.), Nagano 399-4598, Japan; and Institute of Biochemistry,
Hebrew University of Jerusalem (A.R.), Jerusalem 76100,
Israel
Address all correspondence and requests for reprints to: Dr. Chen Chen, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia. E-mail: chen.chen{at}med.monash
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Abstract
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Leptin is produced primarily in adipocytes and regulates body
energy balance. A close link between leptin and pituitary hormones,
including GH, has been reported. The mechanisms employed by leptin to
influence somatotropes are not clear, however. Here we report a direct
action of recombinant ovine leptin on primary cultured ovine
somatotropes by analyzing the levels of mRNA encoding for GH or the
receptors for GHRH (GHRH-R) and GH-releasing peptides (GHRP). Treatment
of ovine somatotropes with leptin (10-7–10-9
M) for 1–3 d reduced the mRNA levels encoding GH and
GHRH-R, but increased GHRP receptor mRNA levels in a time- and
dose-dependent manner. Three-day treatment of cells with leptin
decreased the GH response to GHRH stimulation, but the GH response to
GHRP-2 stimulation was increased. The combined effect of GHRH and
GHRP-2 on GH secretion was not altered by treatment of the cells with
leptin. These results demonstrated a direct action of leptin on ovine
pituitary cells, leading to a reduced sensitivity of somatotropes to
GHRH. It is also suggested that GHRP may be useful to correct the
decrease in GHRH-induced GH secretion by leptin.
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Introduction
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LEPTIN HAS BEEN reported to regulate the
levels of several pituitary hormones in rats, humans, and sheep
(1, 2, 3) in addition to its role in the regulation of food
intake and energy expenditure (4). In the pituitary gland,
leptin is particularly linked to GH, an anabolic hormone
(3). Expression of leptin receptor mRNA has been
demonstrated in the anterior pituitary gland and hypothalamus by RT-PCR
(5, 6). Recently, leptin receptor-like immunoreactivity
has also been detected in about 70% of ovine somatotropes, but has
only been observed in about 20% of gonadotropes or corticotropes in
ovine pituitary gland (7). Furthermore, it has been
reported that leptin receptor gene expression was increased by GH and
GHRH in GHRH transgenic mice (8, 9). In individuals who
are obese due to a truncated mutation of the leptin receptor, a high
level of plasma leptin was proposed to cause a pituitary dysfunction
(10). This observation emphasizes the important role of
leptin in regulating pituitary function. Both long- and short-form
leptin receptor isoforms have been identified by RT-PCR and in
situ hybridization in human pituitaries, which also provides
supporting evidence for a functional role of leptin in the human
pituitary (11, 12).
GH is released from the pituitary gland under the dual control of
hypothalamic somatostatin and GHRH. The cloning of the receptor for
synthetic GH-releasing peptides (GHRP) and recent identification of the
endogenous GHRP, ghrelin, suggest an additional endogenous GH
secretagogue system other than GHRH for the control of GH release
(13, 14). Clinical observation indicates that compared
with normal weight men, obese patients have defects in pulsatile GH
secretion resulting in hyposomatotropism (15, 16). In
addition, the GH response to GHRH stimulation is decreased in obese men
and women, whereas fasting or weight loss tends to restore this
response (17, 18). We postulate that GH secretion can be
regulated by altering the sensitivity of somatotropes to GHRH and/or
GHRP. We therefore investigated the direct effect of leptin on
pituitary somatotropes with a focus on the regulatory mechanism
employed by GHRH and GHRP.
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Materials and Methods
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Ovine pituitary cells
Ovine pituitary cells (dispersed by collagenase treatment) were
subjected to Percoll gradient centrifugation to enrich the somatotrope
population to 60–80% of the total cells (19). The
somatotrope-enriched cells were then cultured in DMEM containing 10%
sheep serum and 2% FCS in 48-well culture dishes (1–2 x
105 cells/well) for incubation experiments
testing GH secretion. Extraction of total RNA was performed on 6-well
(35-mm diameter well) culture dishes (2–3 x
106 cells/well) for RT-PCR reactions. Cell
culture medium was replenished every 2 d during a culture period
of less than 10 d.
Leptin treatment
Treatment of cells with the recombinant ovine leptin
(ro-leptin) was performed on the third day of culture after
replenishing the culture medium. Final concentrations of
ro-leptin in culture medium were
10-9, 10-8, or
10-7 M, and the cells were
treated for 24, 48, or 72 h, with fresh replenishment of culture
medium and ro-leptin once every 24 h. The control group
cells received vehicle alone.
Ovine GH secretion and RIA
On the day of the experiment the culture medium in 48-well
culture dishes was changed to the incubation medium (without serum; the
pH value of medium buffered by 15 mM HEPES) for the GH
secretion assay. Incubation medium for the first 1.5 h at 37 C was
discarded (equilibration time), and then GHRH, GHRP-2, or both were
added to replenished incubation medium for 60-min incubation at 37 C.
The conditioned medium was then collected for ovine GH RIA using
materials supplied by the National Hormone and Pituitary Program,
NIDDK, NIH [ovine GH (RIA) and ovine GH antisera]. The sensitivity of
the assay was 0.25 ng GH/ml, and 50% displacement on the standard
curve was observed at 9.6 ng GH/ml. The intraassay coefficients of
variation for pools containing 9.2 and 3.4 ng GH/ml were 5.3% and
9.4%, respectively (n = 6). The interassay coefficient of
variation was 14.2% (n = 6). All samples from one incubation
experiment were measured in the same assay. GH values were expressed as
nanogram equivalents of the ovine GH standard.
Semiquantitative RT-PCR
The total RNA from cultured cells in 6-well culture dishes with
or without leptin treatment was extracted for GH, GHRH receptor
(GHRH-R), and GHRP receptor (GHRP-R) mRNA assays. RT followed by PCR
amplification was employed to measure levels of ovine GH, GHRH-R, and
GHRP-R mRNA. One microgram of total RNA extracted from each cell
culture well was treated with deoxyribonuclease I to eliminate possible
contamination of genomic DNA. The RNA was then reverse transcribed to
cDNA in a 20-µl RT reaction system containing random primers and
avian myeloblastosis virus reverse transcriptase. The RT reaction was
carried out at 46 C. Two microliters of the RT products were used for
subsequent PCR amplification for 28–32 cycles, which was in the linear
increasing phase of the PCR products. Primers specific for ovine GH,
GHRH-R, and GHRP-R are shown in Table 1
.
RT-PCR was performed as previously described (20).
Twenty-eight cycles of PCR amplification at a 66 C annealing
temperature were used for GHRH-R, 32 cycles at a 62 C annealing
temperature for GHRP-R, and 30 cycles with a 60 C annealing temperature
for GH. All PCR for GH, GHRH-R, and GHRP-R were coamplified with
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (product size, 562
bp), which is the housekeeping gene used as an internal control. Twenty
microliters of PCR products were resolved in a 2% agarose gel, and the
DNA was visualized by ethidium bromide staining and analyzed using NIH
image software, where band intensity is expressed in pixels. Nonreverse
transcribed RNA was included with the primer sets as a negative
control. The relative levels of ovine GH, GHRH-R, GHRP-R mRNA, and
GAPDH mRNA were calculated.
Statistical analysis
Data are presented as the mean (±SEM) of three to
five separate experiments with the same treatment protocol. Comparisons
were made between different treatment groups using ANOVA followed by
the Dunnett post-hoc test for differences from control. Data
for percent changes were analyzed using the Kruskal-Wallis H test. All
experiments conformed to the National Health and Medical Research
Council (Australia) ethics code of practice.
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Results
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Effect of leptin treatment on GH synthesis
Compared with vehicle treatment, 24-h treatment of somatotropes
with ro-leptin (10-7
M) significantly (P < 0.01)
decreased the levels of GH mRNA, although lower doses of
ro-leptin did not reduce the level of GH mRNA (Fig. 1). Three-day treatment of somatotropes
with ro-leptin, however, significantly (P <
0.01 or P < 0.05) reduced the level of GH mRNA at all
three doses of ro-leptin (10-7,
10-8, and 10-9
M) in a dose-dependent manner (Fig. 1). Two-day
treatment with the ro-leptin significantly reduced the
levels of GH mRNA at two doses (10-7 and
10-8 M; Fig. 1).
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Figure 1. The effect of leptin treatment on the level of GH
mRNA. Cells were treated with ro-leptin
(10-7, 10-8, and 10-9
M) for 1, 2, or 3 d before total RNA was extracted.
The top band is GAPDH (562 bp), and the lower
band is GH (437 bp). The levels of GH mRNA were corrected by
GAPDH mRNA. M, Molecular size ladders (650, 500, and 400 bp). The
column represents the mean ± SEM of three separate
experiments. *, P < 0.05; **,
P < 0.01 (vs. control group).
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Effect of leptin treatment on GHRH-R synthesis
Similar to the change in GH mRNA levels after leptin treatment,
levels of GHRH-R mRNA were also reduced by 1-d treatment of cells with
10-7 M, 2-d treatment of cells with
10-7 and 10-8
M, and 3-d treatment of cells with
10-7–10-9 M
ro-leptin (Fig. 2). The
reduction in GHRH-R mRNA levels after 3 d of treatment with
ro-leptin was also dose dependent (Fig. 2).
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Figure 2. The effect of leptin treatment on the level of
GHRH-R mRNA. Cells were treated with ro-leptin
(10-7, 10-8, and 10-9
M) for 1, 2, or 3 d before total RNA was extracted.
The top band is GAPDH (562 bp), and the lower
band is GHRH-R (467 bp). The levels of GHRH-R mRNA were
corrected by GAPDH mRNA. The column represents the mean
± SEM of three separate experiments. *,
P < 0.05; **, P < 0.01
(vs. control group).
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Effect of leptin treatment on GHRP-R synthesis
The effect of ro-leptin on the levels of GHRP-R mRNA
was different from that on GH or GHRH-R mRNA levels. Treatment of
cultured cells with up to 10-7
M ro-leptin for up to 2 d did not
significantly change the levels of GHRP-R mRNA (Fig. 3). Three-day treatment of the cells with
ro-leptin, however, significantly (P < 0.01
or P < 0.05) increased the levels of GHRP-R mRNA in a
dose-dependent manner (Fig. 3).
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Figure 3. The effect of leptin treatment on the levels of
GHRP-R mRNA. Cells were treated with ro-leptin
(10-7, 10-8, and 10-9
M) for 1, 2, or 3 d before total RNA was extracted.
The top band is GHRP-R (659 bp), and the lower
band is GAPDH (562 bp). The levels of GHRP-R mRNA were
corrected by GAPDH mRNA. The column represents the
mean ± SEM of three separate experiments. *,
P < 0.05; **, P < 0.01
(vs. control group).
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Effect of leptin treatment on basal and stimulated GH
secretion
As the level of GH in somatotropes and the density of GHRP-R and
GHRH-R on somatotrope membranes determines GHRH- and GHRP-stimulated GH
release, we tested the effect of GHRP and GHRH on GH secretion. After
treatment of primary cultured cells with ro-leptin
(10-8 M) for 3 d,
basal GH secretion was not changed (control cells, Fig. 4), although the levels of GH mRNA were
decreased by this treatment (Fig. 1
). GHRH (10-8
M)-induced GH secretion was significantly
decreased by 3-d treatment of cells with ro-leptin (Fig. 4).
This treatment also significantly enhanced GHRP-2
(10-8 M)-stimulated GH
secretion (Fig. 4). When both GHRH and GHRP-2 were added to the
incubation medium, the stimulated GH secretion was not changed by
ro-leptin treatment (Fig. 4).
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Figure 4. GH secretion by cultured ovine somatotropes
(2 x 105 cells) in response to 60-min GHRH, GHRP-2,
or combined GHRH and GHRP-2 stimulation. *, P <
0.05 vs. control; **, P < 0.01
vs. control;  , P < 0.05
vs. nonleptin-treated with same stimulation of
secretagogues.
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Discussion
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The present studies demonstrated a direct effect of leptin on
pituitary somatotropes. This reinforces and extends the concept that
leptin regulates pituitary endocrine function. The receptors for leptin
have been shown in the anterior pituitary glands of different species
(6). In sheep, more than 60% of somatotropes exhibit
positive staining using antibodies against the leptin receptor, whereas
only 20% of gonadotropes or corticotropes had positive staining for
the leptin receptor (7). The level of leptin receptor in
the pituitary gland is markedly up-regulated in GHRH transgenic mice
(8), which suggests a link between GHRH/GH levels and the
sensitivity of pituitary cells to leptin. The effect of leptin on GH
levels, however, is controversial depending on the experimental animal
species, nutritional conditions, and delivery method of leptin. It has
been reported that 7-d intracerebroventricular (icv) infusion of leptin
increased both the nadir level and pulse amplitude of GH in male rats
(21). However, a different laboratory reported that the
icv injection of leptin for 3 d did not change GH levels in
normally fed rats (22). Intracerebroventricular injection
of antibodies against rat leptin reduced GH secretion
(23), whereas icv administration of leptin protected
against the inhibitory effect of restricted nutrition on GH secretion
in the rat (22, 23). It is worthwhile to emphasize that
restricted nutrition in sheep or humans has a stimulatory effect on
circulating GH levels (24, 25). Thus, one might expect
that leptin would act on the pituitary somatotropes to reduce GH
secretion in sheep and humans. This appears to be true for
GHRHstimulated GH secretion from primary cultured ovine
somatotropes (3, 26) and may be synonymous with the
reduced level of GH seen in obese individuals (25).
The experiments reported in this manuscript have further clarified the
mechanism for the reduction in GHRH-stimulated GH secretion by leptin.
Levels of both GH and GHRH-R mRNA were significantly reduced by
ro-leptin, and such a decline in mRNA levels was leptin dose
and time dependent. After 3 d of treatment of cells with
ro-leptin, all three doses of leptin employed in the
experiments (1, 10, and 100 nM) significantly
reduced GH and GHRH-R mRNA levels in cultured somatotropes. These
changes in the levels of GH and GHRH-R mRNA suggest a decrease in the
synthesis of GH and GHRH-R in ro-leptin-treated
somatotropes. Such a decrease in the synthesis of GH and GHRH-R may
lead to a decrease in GH accumulated in somatotropes and a decrease in
GHRH-R density on the surface of somatotropes. These changes may
therefore evoke a decrease in GHRH-stimulated GH secretion. As this has
been achieved in primary cultured somatotrope-enriched (60–80% of
total cells are somatotropes) cells, the action of leptin reported here
is most likely a direct action on pituitary somatotropes without
involvement of any hypothalamic, peripheral, or paracrine factor. Basal
secretion of GH was not affected by the treatment of cells with
ro-leptin, although the GH mRNA level was decreased. This
may indicate that basal GH secretion is maintained even after
ro-leptin treatment.
In contrast to the decline in the levels of GH and GHRH-R mRNA, the
level of GHRP-R mRNA is increased by 3-d treatment of ovine
somatotropes with ro-leptin. This indicates an increase in
the synthesis of GHRP-R. In this experiment GHRP-2-induced GH secretion
was increased after 3-d treatment of cells with ro-leptin.
This result suggests that the increase in the synthesis of GHRP-R by
ro-leptin enhances the GH response to GHRP-2, possibly
through an increase in receptor density on the membrane of
somatotropes. The combined effect of GHRH and GHRP-2 on GH secretion
was not changed by 3-d leptin treatment of somatotropes. This indicates
that the action of GHRP-2 can completely compensate for the decrease in
GH response to GHRH after treatment of cells with leptin for 3 d.
One recent report indicates that the level of endogenous GHRP (or
ghrelin) is significantly lower in obese humans compared to normal
weight counterparts (27), which suggests GHRP deficiency
in overweight conditions. This report also supports our view that GHRP
may be a useful therapeutic drug to treat GH deficiency in obesity
patients.
The level of leptin in human plasma is 5–20 ng/ml in normal
weight population and increases to 600 ng/ml in obese individuals
(28, 29). The dose range of leptin used in this
experiment (1–100 nM or 16 ng/ml to 1.6 µg/ml) is in
the range of plasma leptin concentrations in obesity patients. Leptin
is secreted in pulses and in a nyctohemeral rhythm (30),
and the peak value of leptin may be even higher than 600 ng/ml in obese
individuals. It is also possible that the local concentrations of
leptin in hypothalamic-pituitary portal blood or in anterior pituitary
glands may be higher that the plasma levels.
Previously, the site of leptin action was not clear; in particular,
whether it acted on pituitary cells has remained obscure. Here we
demonstrated a direct action of leptin on pituitary somatotropes
influencing the sensitivity of somatotropes to GHRH and GHRP
stimulation. The cellular mechanism of leptin action on endocrine cells
is another focus of this study. Previous research has mostly examined
effects on hormone levels in response to leptin treatment in whole
animal experiments, with little attention to changes in endocrine cell
function. Here we demonstrated that leptin actually modified the
cellular function of pituitary somatotropes by changing the synthesis
of GH, GHRH-R, and GHRP-R.
In summary, the current experiments provide evidence for the direct
action of leptin on pituitary somatotropes to modify the cell function
and sensitivity to GHRH and GHRP by altering the synthesis of GH and
receptors for GHRH and GHRP. The effect of combined GHRH and GHRP on GH
secretion is not influenced by leptin treatment, suggesting a possible
use of GHRP in the treatment of GH deficiency in obese patients.
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Acknowledgments
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We thank Ms. S. Panckridge for assistance with the preparation
of graphics for this manuscript. We also thank Drs. I. J. Clarke
and J. W. Goding for scientific discussion, and Drs. B. D.
Gaylinn and M. O. Thorner for providing the ovine GHRH-R sequence.
We express special thanks to Dr. P. Stanton for his careful reading and
revision of the manuscript.
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Footnotes
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This work was supported by the Australian National Health and Medical
Research Council and in part by a grant from the Aza Research Pty. Ltd.
(Australia).
Abbreviations: GAPDH, Glyceraldehyde-3-phosphate dehydrogenase;
GHRH-R, GHRH receptor; GHRP, GH-releasing peptide; GHRP-R, GH-releasing
peptide receptor; icv, intracerebroventricular;
ro-leptin, recombinant ovine leptin.
Received May 21, 2001.
Accepted for publication September 5, 2001.
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F. Rodriguez-Pacheco, R. Vazquez-Martinez, A. J. Martinez-Fuentes, M. R. Pulido, M. D. Gahete, H. Vaudry, F. Gracia-Navarro, C. Dieguez, J. P. Castano, and M. M. Malagon
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C. Crane, N. Akhter, B. W. Johnson, M. Iruthayanathan, F. Syed, A. Kudo, Y.-H. Zhou, and G. V. Childs
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F. Rodriguez-Pacheco, A. J. Martinez-Fuentes, S. Tovar, L. Pinilla, M. Tena-Sempere, C. Dieguez, J. P. Castano, and M. M. Malagon
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D. D. Feng, Z. Luo, S.-g. Roh, M. Hernandez, N. Tawadros, D. J. Keating, and C. Chen
Reduction in Voltage-Gated K+ Currents in Primary Cultured Rat Pancreatic {beta}-Cells by Linoleic Acids
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M. C. French, R. P. Littlejohn, G. J. Greer, W. E. Bain, J. C. McEwan, and D. J. Tisdall
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I. A. McDuffie, N. Akhter, and G. V. Childs
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Y. Sandowski, N. Raver, E. E. Gussakovsky, S. Shochat, O. Dym, O. Livnah, M. Rubinstein, R. Krishna, and A. Gertler
Subcloning, Expression, Purification, and Characterization of Recombinant Human Leptin-binding Domain
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H. Watanobe and S. Habu
Leptin Regulates Growth Hormone-Releasing Factor, Somatostatin, and alpha -Melanocyte-Stimulating Hormone But Not Neuropeptide Y Release in Rat Hypothalamus In Vivo: Relation with Growth Hormone Secretion
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Top
Abstract
Introduction
