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Department of Molecular Genetics (D.B., M.R.), Weizmann institute of Science, Rehovot 76100, Israel; Department of Molecular Cell Biology (H.J., A.D., A.A.), Weizmann institute of Science, Rehovot 76100, Israel; and Department of Biochemistry (L.V.), Tel Aviv University, Tel Aviv 69978, Israel
Address all correspondence and requests for reprints to: Prof. Menachem Rubinstein, Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: lvrub{at}weizmann.weizmann.ac.il
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-hydroxy-4-pregnen-3-one was inhibited by leptin. This inhibition
was due at least in part to reduced expression of adrenodoxin, a
component of the P450scc system enzyme. Costimulation of progesterone
production by forskolin and dexamethasone was also inhibited by leptin,
whereas the forskolin-induced cAMP production was not affected. We find
that leptin induces c-Jun expression and attenuates the transcriptional
activity of the glucocorticoid receptor (GR) in granulosa cells.
Elevation of c-Jun expression by other means, e.g.
12-O tetradecanoyl-phorbol-13-acetate or transfecting
with a c-Jun expression vector, abolished the transcriptional activity
of the GR. A leptin-induced elevation of c-Jun modulates the
transcriptional activity of the GR, possibly leading to the observed
attenuation of steroidogenesis. It was recently shown that
glucocorticoids stimulate leptin expression in vivo,
which in turn, inhibits cortisol synthesis. A direct action of leptin
on the ovary is an additional element of a regulatory network that
maintains the homeostasis of steroid production. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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OB-Rb, the long form of OB-R, is expressed predominately in the hypothalamus, where it mediates many leptin’s activities by regulating metabolic and behavioral activities. Ligand binding to OB-Rb activates Janus kinase 2 and its substrates STAT-1, STAT-3, and STAT-5 (5, 6). COS cells transfected with either the shorter variant OB-Ra or OB-Rb express the immediate early genes such as c-Jun, c-Fos, and Jun B upon treatment with leptin (7). OB-Ra is expressed in various tissues, and therefore leptin may exert other physiological functions by acting directly on peripheral cells and tissues. Indeed, it has been shown that leptin exerts various activities on peripheral targets such as liver cells, pancreatic ß-cells, and muscle cells (8, 9, 10).
Several studies have shown that leptin also plays a major role in reproduction. For example, leptin treatment rescued the sterility of genetically obese ob/ob mice (11, 12). In addition, leptin accelerated the onset of puberty in female mice (13). Because leptin levels are correlated with body mass index, it appears that leptin acts as a message, informing the brain that maternal energy stores are sufficient to support the high-energy demands of reproduction. Recently, it has been reported that the messenger RNA of the long and short forms of leptin receptors are present in granulosa and cumulus oophorus cells (14), suggesting that leptin may have a direct effect on ovarian function.
Granulosa cells, which differentiate during each estrous cycle and nurse the mammalian egg, are the main site of progesterone production (15). The induction of steroidogenesis in granulosa cells is initiated by the gonadotrophic hormones FSH and LH, which interact with specific cell membrane receptors (16). The interaction of these gonadotropins with their receptors leads to the activation of adenylate cyclase and subsequently to the induction of steroidogenic enzymes such as cytochrome P450 side chain cleavage enzyme (P450scc) and its ancillary electron transport proteins adrenodoxin (ADX) and ADX reductase (17, 18). P450scc catalyses the first step in the biosynthesis of progesterone by converting cholesterol to pregnenolone. (15).
The mechanism by which steroidogenesis is induced cannot be solely attributed to the action of the gonadotropins. Additional substances, including growth factors and corticosteroids are known to modulate gonadotropin’s activity (19, 20, 21). For example, it was shown that glucocorticoids augment the FSH-induced production of progesterone in rat preantral primary granulosa cells (19). Glucocorticoids also stimulate leptin expression in adipocytes, whereas leptin inhibits glucocorticoid synthesis in the adrenal cortex (22, 23). This regulatory feedback prompted us to study the direct effect of leptin on the glucocorticoid response in granulosa cells. We report here that leptin inhibits the glucocorticoid augmentation of steroid synthesis in granulosa cells. A leptin-induced c-Jun expression is possibly involved in this process.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human granulosa cells (clone HO23) were immortalized by cotransfection with SV40, Ha-ras, and a p53 temperature-sensitive mutant (p53 val 135), (26). Cells were cultured and stimulated as described for FSHR-17 cells.
Plasmids
Plasmid p
G46TCO contains two copies of a synthetic
glucocorticoid receptor response element (GRE) linked to the herpes
virus thymidine kinase (TK) promoter, followed by a chloramphenicol
acetyl transferase (CAT) gene (27). Plasmid pRSVc-Jun for mammalian
expression of c-Jun and the control plasmid pRSV-ß Gal were
previously described (28, 29).
DNA transfection
FSHR-17 cells (1 x 105 cells) in 30-mm plates
were transfected with various plasmids with the aid of the FuGENE
transfection reagent (Boehringer Mannheim, Mannheim,
Germany). Eighteen hours after transfection, the medium was
replaced with fresh DMEM/F12 medium containing 10% FBS, and the
transfected cells were cultured for an additional 24 h in the
presence or absence of various stimulants.
CAT assay
CAT activity was determined as described (29). After
transfection and various treatments, sonicates of FSHR-17 cells were
heated for 10 min at 65 C before analysis. CAT activity in various
cells was adjusted to the same amount of protein. The percentage of
chloramphenicol acetylation was calculated by scanning the TLC plates
with a phospho-imager. The value of CAT activity in cells treated with
dexamethasone (DEX) only was used to normalize all other results.
cAMP assay
Intracellular cAMP levels were determined in extracts of cells
that were cultured with [3H]-adenine. Preformed
monolayers of FSHR-17 cells in 24-well plates (2 x
104 cells) were incubated for 16 h in a serum-free
medium containing [2-3H]adenine (10 µCi/ml). The medium
was then replaced by a serum-free medium (0.5 ml) containing the
appropriate stimulant. After 15 min the medium was discarded and
ice-cold perchloric acid (2.5%) containing 0.1 mM cAMP (1
ml/well) was added. The perchloric acid extract was neutralized with 1
M Tris/4.2 M KOH, [2-3H]-cAMP was
isolated by sequential chromatography on a Dowex-50 cation exchanger
and neutral alumina. Intracellular accumulation of
[2-3H]-cAMP was calculated as the percentage of total
[2-3H]-adenine uptake per well (30).
Progesterone assay
FSHR-17 or primary rat preovulatory granulosa cells were
cultured in 24-well plates in DMEM/F12 medium containing 10% FBS.
After 18 h the medium was replaced by a serum-free medium
containing the desired stimulant. Progesterone accumulation in the
culture medium was determined after 24 h by RIA (31).
Immunoblot assay of ADX
FSHR-17 cells were plated in 60-mm dishes (4 x
105 cells/dish) in DMEM/F12 medium containing 10% FBS.
After 18 h the medium was replaced by a serum-free medium
containing the desired stimulant. After 24 h, the cells were
washed and pelleted (1500 x g, 10 min). The pellets
were lysed for 15 min at 4 C in Lysis Buffer (0.1 ml of 50
mM HEPES, pH 7.4, 150 mM NaCl, 1 mM
MgCl2, 1 mM EGTA, 1 mM EDTA, 1%
Triton X-100, 10% glycerol, 1 mM Na orthovanadate, 5
µg/ml aprotinin, 1 nM phenylmethanesulfonyl fluoride, 20
mM NaF). The clarified extracts (30 µg protein) were
separated by 12% SDS-PAGE, transferred to nitrocellulose membrane and
probed with a polyclonal antibody against ADX (1:1000), followed by
goat antirabbit antibody conjugated to horseradish peroxidase
(Jackson Laboratories, Bar Harbor, ME). The complexes were
visualized by the enhanced chemiluminescence (ECL,
Amersham) and quantitated by densitometry.
Immunoblot analysis of AP1
FSHR-17 cells were plated in 60-mm dishes (4 x
105 cells/dish) in DMEM/F12 medium containing 10% FBS and
incubated for 18 h. The medium was then replaced by a serum-free
medium and the cultures incubated for additional 24 h. The medium
was then replaced by a serum-free medium containing the desired
stimulant and nuclear extracts were prepared after 2 h by the
following procedure: washed cell pellets were resuspended for 15 min at
4 C in 0.4 ml hypotonic buffer (10 mM HEPES, pH 7.9, 10
mM KCl, 1 mM EDTA, 1 mM EGTA, 1
mM DTT, 0.1 mM p-amino benzoic acid, 1
mM PMSF, 10 µg/ml leupeptin, 1 µg/ml pepstatin and 50
µg/ml aprotinin). Triton X-100 (10%, 25 µl) was then added and the
suspension was mixed vigorously for 10 sec. The nuclei were separated
from the cytoplasmic fraction by centrifugation (15,000 x
g, 30 sec, 4 C). The nuclear fraction was then extracted by
resuspending it in 0.2 ml ice cold nuclear extraction buffer (20
mM HEPES, pH 9.7, 400 mM NaCl, 1 mM
EDTA, 1 mM EGTA, 1 mM DTT, 0.1 mM
p-amino benzoic acid, 10 µg/ml leupeptin, 1 µg/ml pepstatin, 50
µg/ml aprotinin, and 1 mM PMSF). After rotating the tubes
for 15 min at 4 C the nuclear extract was cleared by centrifugation.
Nuclear extracts (30 µg protein) were separated by 12% SDS-PAGE,
transferred to a nitrocellulose membrane and probed with a rabbit anti
c-Jun/AP1 antibody, followed by goat antirabbit antibody conjugated to
horseradish peroxidase. The bands were visualized by the enhancer
chemiluminescence kit (Amersham) and quantitated by
densitometry.
Antibodies and other reagents
Antibodies against pregnenolone, progesterone and
20,hydroxy-4-pregnen-3-one were a kind gifts from Dr. F. Kohen,
Weizmann Institute of Science (Rehovot, Israel). Polyclonal antibody
against adrenodoxin was kindly provided by Dr. W. L. Miller,
University of California (San Francisco, CA). Rabbit c-Jun/AP1
polyclonal antibody was from Santa Cruz Biotechnology, Inc.; DEX, 2-O-tetradecanoyl-phorbol-13-acetate (TPA)
and forskolin were from Sigma Chemical Co. (St. Louis,
MO). Human recombinant FSH was from the National Institute of Health
(Bethesda, MD). Murine leptin was from PeproTech Inc. (Rocky Hill, NJ).
Human leptin was the kind gift of R. Devos and Y. Guisez, Roche
Gehnt.
Statistical significance
All experiments were repeated at least three times with
different batches of cells. Values are the mean ± SE
of these experiments where noted. Significance between experimental
values was determined by unpaired Student’s t test and are
significant if P value were <0.05 when data from all
experiments were considered.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
Inhibition was dose-dependent with the maximal effect obtained at 18
nM leptin (Fig. 2A). This
inhibitory effect of leptin was obtained also in the rat granulosa cell
line FSHR-17, where leptin lowered the levels of progesterone in a
dose-dependent manner, with a maximal effect of murine leptin obtained
at 0.6 nM (P < 0.05, Fig. 2B).
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). Similar results were obtained with
rat primary granulosa cells (30% inhibition, P <
0.05; Fig. 3B) and with human HO23 cells (34% inhibition,
P < 0.05; Fig. 3C). The higher concentration of leptin
needed for attenuating the forskolin-induced cells as compared with
FSH-induced cells may be attributed to the observation that FSH exerts
only a transient increase of cAMP in the rat granulosa cells, whereas
forskolin was shown to induce a sustained and potent rise of cAMP in
these cells (24).
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). Leptin at a
physiological concentration range (32) suppressed the level of
progesterone induced by FSH and DEX. In contrast, at higher
concentrations, leptin elevated the level of progesterone, rather than
further suppressing it. However, leptin alone did not induce any change
in the progesterone level, even when added at high concentrations (>60
nM) (Figs. 1 and 2B).
Leptin may reduce progesterone levels in granulosa cells either by
inhibition of its synthesis or by enhancing its metabolism (33). To
distinguish between these two possibilities, we determined the effects
of leptin on the levels of the progesterone precursor pregnenolone, as
well as the progesterone metabolite 20 hydroxy-4-pregnen-3-one. The
levels of both the precursor and the metabolite were reduced by 32%
and 40%, respectively (P < 0.05 in both cases) when
leptin (2 nM) was added to cultures of FSHR-17 cells
costimulated by FSH and DEX (Fig. 4A).
These results suggest that in rat granulosa cells leptin inhibits
progesterone synthesis rather than enhancing its further
metabolism.
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, compare lane 5 with lanes 6, 7, and 9), whereas leptin (60
nM) down-regulated by 2.1 ± 0.31-fold the forskolin +
DEX-induced expression of ADX (P < 0.05, n = 3,
compare lane 9 with lanes 11 and 12). Neither leptin alone nor DEX
alone affected ADX expression (lanes 3 and 4). Furthermore, leptin had
no significant effect on the forskolin-induced level of ADX (n =
3, compare lane 5 with lane 8).
Leptin attenuates the transcriptional activity of the
glucocorticoid receptor
Both P450scc system enzyme and its product progesterone may be
induced by FSH or forskolin in the absence of DEX. Therefore, it is
possible to determine if leptin modulates the activity of either
FSH/forskolin or that of glucocorticoids. We found that leptin did not
affect the level of forskolin-induced ADX in FSHR-17 cells (Fig. 4B, compare lane 5 with lane 8). Similarly, we found that leptin had no
effect on the basal and forskolin-induced progesterone production in
FSHR-17 cells (P > 0.05, Fig. 5A), nor did it affect (P
> 0.05) the basal and forskolin-induced production of cAMP in these
cells (Fig. 5B). We therefore concluded that leptin does not affect the
induction of cAMP by FSH or forskolin and their subsequent effect on
steroidogenesis. Rather, it is likely that leptin inhibits the
DEX-induced pathway.
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G46TCO,
containing a GR response element, the TK promoter, and the CAT gene
(27). Transfected cells were treated for 24 h with DEX in the
presence or absence of leptin and the level of CAT was then determined.
Leptin (60 nM) was found to significantly inhibit CAT
activity induced by DEX (35% inhibition, P < 0.05),
whereas leptin alone had no effect on CAT activity (Fig. 6). Thus leptin probably lowers the
expression of the ADX gene by attenuating the transcriptional activity
of GR.
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). c-Jun levels
remained significantly higher than untreated cells 6 and 24 h post
treatment (data not shown).
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G46TCO, and the expression vector pRSVc-Jun. As a control,
cells were cotransfected with pRSV-ßGal and pG46TCO. Transfected
cells were cultured with or without DEX for 24 h and then assayed
for CAT activity. In addition, the steady-state level of c-Jun was
elevated by treatment of GRE-CAT-transfected cells with TPA (100
nM, 24 h) followed by DEX. Both over-expression of
c-Jun or elevation of c-Jun by TPA abolished the DEX-induced CAT
activity, whereas transfection of FSHR-17 cells with the control
plasmid pRSV-ßGal had no inhibitory effect on GR activity (Fig. 7B).
Furthermore, the c-Jun inducer TPA also inhibited progesterone
synthesis in FSHR-17 cells (Fig. 7C). Induction of progesterone
synthesis by forskolin alone was inhibited by >50% (P
< 0.05), whereas the DEX-augmented induction was inhibited by 93%
(P < 0.01). Similarly, TPA (50 nM)
inhibited the forskolin induced expression of ADX by 1.6 ±
0.15-fold (P < 0.001, n = 3, Fig. 7D, compare
lane 3 with lane 4), whereas the forskolin + DEX-augmented induction of
ADX was reduced by 3 ± 0.65 fold (P < 0.05,
n = 3, compare lane 5 with lane 6). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A minimal level of leptin is required for activating the hypothalamic-pituitary axis, which triggers gonadotropin secretion. Indeed, lack of leptin due to starvation or due to a genetic defect (e.g. in ob/ob mice), or lack of the hypothalamic leptin receptor (as in db/db mice), all lead to gonadotropin deficiency and unovulation (11). The local effects of leptin on ovarian steroidogenesis are in opposite direction to its central effects. Thus, leptin was previously reported to inhibit steroid synthesis in granulosa cells when induced by FSH in combination with growth factors such as IGF-I and insulin (38, 39). It was also found recently that leptin inhibits the LH-induced estradiol production in rat granulosa cells (40). We show here for the first time that DEX-stimulated production of progesterone in FSH-treated primary rat granulosa cells is inhibited in a dose-dependent manner by leptin at physiological concentrations (0–20 nM). At high, nonphysiological levels, the inhibition was attenuated, indicating that leptin may act by multiple mechanisms. Thus, at physiological concentrations, leptin seems to attenuate locally the steroidogenic activity of various signals that enhance FSH activity. Hence, the homeostasis of steroid production in granulosa cells is maintained by the opposite local and central effects of leptin. These regulatory mechanisms are part of a complex network, which also includes the induction of leptin expression in adipocytes by glucocorticoids (22) and the inhibition of glucocorticoid synthesis in the adrenal cortex by leptin (23).
The molecular events leading to attenuation of steroidogenesis by
leptin were studied in FSHR-17 cells. Our findings that leptin inhibits
the production of pregnenolone, the precursor of progesterone, as well
as the progesterone metabolite 20-hydroxy-4-pregnen-3-one, indicates
that leptin may act as an inhibitor of ovarian steroidogenesis. Becuase
leptin had no effect on the basal and the forskolin-induced
progesterone and cAMP production, we tested if leptin affects the
cellular response to glucocorticoids. Glucocorticoids were reported to
augment the gonadotropin-induced transcription of P450scc in a Leydig
tumor cell line (41). Therefore, we studied the effect of leptin on the
transcriptional activity of GR. We found that glucocorticoids augment
the cAMP induced transcription of ADX in FSHR-17 cells and leptin
inhibits this activity. Thus, our finding that leptin attenuates the
transcriptional activity of GR is a possible mechanism by which leptin
modulates the expression of ADX, thereby lowering ovarian steroid
synthesis. Perhaps leptin can also modulate the expression of other
steroidogenic enzymes such as P450scc, 3ß-hydroxysteroid
dehydrogenase/5-4 Isomerase or 20
-hydroxysteroid dehydrogenase. Alternatively, leptin may affect the
expression of the steroidogenic acute regulatory protein (StAR) (42),
steroidogenic transcription factor SF-1/Ad4BP (43) or Sterol Carrier
Protein 2 (SCP2) (44).
The mechanism by which activated GR elevates ADX remains to be elucidated. DEX effectively induces ADX in FSHR-17 cells but the promoter region of the rat ADX gene was not cloned. The activated GR may induce the transcription of ADX gene by directly binding to a classical or variable GRE (45, 46) in the ADX promoter. Alternatively, DEX may induce the transcription of ADX indirectly, as was reported for P450scc induction in a Leydig tumor cell line (41).
The AP1 family of transcription factors consists of homodimers and heterodimers of Jun (v-Jun, c-Jun, Jun B, Jun D), Fos (v-Fos, c-Fos, Fos B, Fra1, Fra2) or activating transcription factors (ATF2, ATF3/LRF1, B-ATF) bZIP (basic region leucine zipper) proteins (47). The ability of c-Jun to interact with GR and alter the program of gene expression was shown previously (35, 36). Overexpression of c-Jun has already been shown to repress GR activity in other systems (27). Therefore, our finding that leptin induces the expression of c-Jun in FSHR-17 cells and that the overexpression of c-Jun in these cells abolishes the transcriptional activity of the GR provide one possible explanation how leptin attenuates GR activity, thus reducing the steroid production. Both TPA and leptin induce the expression of c-Jun and attenuate the induction of ADX expression. However, TPA is more potent than leptin as an inhibitor of GR transcriptional activity, as well as an inhibitor of DEX-augmented progesterone production. The lower inhibitory action of leptin suggests that it may transduce in parallel other signaling cascades that could attenuate c-Jun activity. For example, leptin may induce other members of the AP1 family such as Jun D, a potential inhibitor of c-Jun (27).
The GRE-CAT reporter vector used here for determination of the
transcriptional activity of GR (pG46TCO) does not contain an AP1
binding site. Hence, the overexpressed c-Jun must have abolished the
transcriptional activity of the GR by interacting directly with it.
This mode of interaction was previously shown to occur between the
DNA-binding domain of GR and the leucine zipper region of c-Jun (35, 36). The resulting complex could not bind to any one of the cognate DNA
elements in vitro. Alternatively, it is possible that a
GR/c-Jun complex can still bind to a DNA element, but such binding
represses transcription by blocking transactivation (48). We have
excluded another possible mode of GR inhibition, namely,
down-regulation of its expression by leptin (data not shown).
Therefore, the induction of c-Jun in granulosa cells by leptin inhibits
the transcriptional activity of GR, which may lead to a reduced steroid
hormone synthesis.
The signaling mechanism by which leptin up-regulates the steady-state level of c-Jun in granulosa cells remains to be elucidated. c-Jun is frequently subject to transcription-regulation (47). However, new findings have suggested that c-Jun activity can also be regulated by modulating its rate of degradation. Thus, phosphorylation of serine and threonine residues at its amino-terminal activation domain by mitogen-activated protein kinase (MAPK) reduces the ubiquitinylation of this protein and hence its rate of degradation (49). Recent reports have suggested that leptin activates MAPK (50). Thus, induction of MAPK by leptin may account for at least part of its signaling cascade, leading to the activation of c-Jun.
In conclusion, the present data demonstrates that leptin exerts opposite central and local effects on ovarian steroid synthesis. It would be of great interest to find how general is this effect of leptin on the GR, as it may impinge upon the transcription of many other genes, thus giving new insights to the endocrine role of leptin.
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Acknowledgments |
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Footnotes |
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2 Joyce and Ben B. Eisenberg Professor of Molecular Endocrinology and
Cancer Research.
3 Edna and Maurice Weiss Professor of Cytokine Research.
Received July 29, 1998.
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References |
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