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21
Service de Biochimie, INSERM CJF 94–02, Faculté de Médecine Paris-Ouest, Université René Descartes (Paris V) Centre Hospitalier de POISSY, 78303 Poissy Cedex, France
Address all correspondence and requests for reprints to: Y. Giudicelli, Service de Biochimie, Centre Hospitalier, 78303 Poissy Cedex, France. E-mail: rpecq{at}club-internet.fr
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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2 was up-regulated by
17ß-estradiol but not by androgens. As described in other cell types,
sex steroids modulate insulin growth factor 1 receptor (IGF1R)
expression in preadipocytes. Indeed, IGF1R levels were either enhanced
by 17 ß-estradiol (0.01 µM) in sc preadipocytes from
female ovariectomized rats or decreased by DHT (0.01 µM)
in epididymal preadipocytes. These effects were reversed by
simultaneous exposure to androgen or estrogen receptor antagonists. In
conclusion, this study demonstrates that, in rat preadipocytes kept in
primary culture and chronically exposed to sex hormones, androgens
elicit an antiadipogenic effect, whereas estrogens behave as
proadipogenic hormones. Moreover, our results suggest that these
opposite effects could be related to changes in IGF1R (androgens and
estrogens) and peroxisome proliferator-activated receptor 2
expression (estrogens). |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Development of white adipose tissue (adipogenesis) is characterized by
a sequence of events during which adipose precursor cells proliferate
until confluence and then differentiate into mature adipocytes. The
preadipocyte-adipocyte conversion process is induced by the
transcriptional activation of adipose specific genes such as adipsine,
aP2, LPL. (5, 6, 7). Master regulatory transcription factors [peroxisome
proliferator-activated receptor 2 (PPAR2), C/EBP
, C/EBPß,
C/EBP
] are involved in activating or derepressing transcription of
these genes and thus seem to be the key in the commitment of the
differentiation program (8, 9, 10). Adipogenesis is markedly influenced by
a variety of hormones and nutritional signals. Insulin, insulin-like
growth factor 1 (IGF1), GH, and glucocorticoids are important positive
signals for adipocyte differentiation in vivo and in
vitro (11, 12, 13). IGF1, like insulin, stimulates both preadipocyte
growth and differentiation.
The role played by sex hormones in adipogenesis is still poorly understood. In human adipose tissue, estrogens have been reported to modulate adipogenesis in vitro by increasing preadipocyte replication (14) without altering the differentiation process (15). In rat preadipocytes, progesterone stimulates the terminal differentiation (16) whereas, in 3T3-L1 and 3T3-F442A preadipocyte cell lines and in pig preadipocytes, high concentrations of dehydroepiandrosterone (DHEA) and other androgen-related steroids were shown to block the adipose conversion process, as followed by measurement of glycerol-3 phosphate dehydrogenase (GPDH) activity, a late marker of differentiation (17, 18, 19).
Biological effects of steroid hormones are primarily mediated by their specific receptors. Estrogen and androgen receptors are expressed in rat (20, 21, 22) and human (23, 24) preadipocytes and adipocytes. In these cells, the number of estrogen and androgen receptors are also variable, according to their anatomical origin (22, 25, 26), suggesting that preadipocytes and adipocytes are target cells for sex hormones.
The aim of the present study was to get a better understanding of the role of sex hormones in adipogenesis and its relationship to anatomical origin of the preadipocytes. For this purpose, we have compared adipogenesis in primary cultured male and female rat preadipocytes removed from deep and superficial fat depots and exposed or not to sex steroid hormones during either the growth phase or the differentiation process.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-dihydrotestosterone (DHT),
17ß-estradiol, dehydroepiandrosterone (DHEA),
dehydroepiandrosterone sulfate, estrone (1,3,5 [10]-estratrien 3 ol
17 one), androstanediol (5- androstane 3ß, 17ß, diol),
androstenediol (5androstene 3ß, 17ß, diol), and BSA were from
Sigma (St. Louis, MO); ICI182780 was from Tocris (Bristol,
UK); RU23908 was from Roussel-Uclaf (Romainville, France); collagenase
was from Roche Molecular Biochemicals (Mannheim, Germany);
FCS was from Life Technologies (Grand Island, NY);
polyclonal rabbit anti-PPAR2 antiserum was from Affinity BioReagents, Inc. (Golden, CO); polyclonal rabbit anti-IGF1
receptor (anti-IGF1R) antiserum and polyclonal goat anti IGF1 antiserum
were from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA);
and horseradish peroxidase-labeled rabbit anti-IgG was from
Sanofi Pharmaceuticals, Inc. Pasteur (Marne la Coquette,
France).
Animals
Adult male and female Sprague Dawley rats (150–200 g) were kept
under controlled lighting conditions (light, 0600 h; dark,
2000 h) and constant temperature (21 C). Females were
ovariectomized as previously described (27). Animals were killed by
decapitation. Epididymal, parametrial, and femoral sc adipose
tissues were immediately removed under sterile conditions.
Cell culture
Cell preparation and culture were performed as described (22).
Briefly, preadipocytes were obtained by collagenase digestion. The
floating adipocytes were discarded, and the infranatant containing the
stromal vascular fraction was successively filtered through 150- and
25-µm nylon screens. The filtrate was centrifugated at 600 x
g for 10 min. After two washes, cells were plated into cell
culture dishes at a density of 2–4 x 104
cells/cm2 with 8% FCS-DMEM and were maintained
at 37 C under 5% CO2 atmosphere. After plating,
cells were extensively washed and maintained: 1) for the cell growth
experiments, in DMEM with 2% FCS; or 2) for the differentiation
studies, in DMEM with 8% FCS during 2 days and then in
DMEM-F12 (1:1) supplemented with insulin (5 µg/ml), transferrin (10
µg/ml), T3 (2 nM) (ITT
medium), as described (28), until the full differentiation state was
reached (day 9 or 10 after plating).
When added to the medium, steroid hormones were dissolved in ethanol. The same ethanol concentrations were added to control medium (final ethanol concentration never exceeding 0.01%, vol/vol). Cell viability was assessed by the trypan blue exclusion test (29) and by measurement of lactate dehydrogenase activity in the culture medium (30).
The polyclonal anti IGF1 antiserum was used, at 4 µg/ml, to block endogenous and exogenous IGF1 in the culture medium during 3 days post plating.
Growth assays
Cell number was determined at day 3 post plating. Cells were
trypsinized and counted in a hemocytometer.
GPDH assay
Cell differentiation was followed using GPDH activity as a
marker of differentiation. After 9–10 days post plating, ITT medium
was removed, and cells were scraped in cold buffer containing 50
mM Tris-HCl (pH 7.4), 0.25 M sucrose, 1
mM EDTA, and 1 mM dithiothreitol. Cells were
sonicated in the same buffer and centrifuged at 100,000 x
g for 20 min at 4 C. GPDH activity was measured in the
supernatant according to Wise and Green (31) and expressed in mU (nmol
NAD+/min) per mg protein.
Immunoblotting
PPAR protein expression. Differentiated preadipocytes
were scraped and sonicated in cold buffer containing 50 mM
Tris (pH 8), 120 mM NaCl, 1% nonidet P40, 0.5%
deoxycholate, 0.1% SDS, 0.5 mM
phenylmethylsulfonylfluoride, 25 µg/ml aprotinin, and 105
µM leupeptin. After centrifugation at 100,000 x
g for 20 min at 4 C, the resulting supernatant was denatured
with Laemmli buffer (vol/vol) and stored at -20 C.
Cellular extracts (20 µg) were resolved by SDS/PAGE (12.5%
acrylamide). Proteins were transferred to
polyvinylidenedifluoride membranes overnight at 4 C and blocked
for 2 h at room temperature in buffer A (137 mM NaCl,
20 mM Tris-HCl, 0.1% Tween 20) with 5% nonfat dry milk.
Primary polyclonal PPAR1–2 antiserum (1:2000 dilution) was then
added in buffer A and incubated overnight at 4 C. The primary antiserum
was then removed and the blot washed extensively with buffer A.
Secondary antiserum (horseradish peroxidase-labeled antirabbit
IgG) was added (1:4000 dilution) and incubated with the blot for 1
h at room temperature. After washing, an enhanced chemiluminescence kit
from Amersham Pharmacia Biotech (Aylesbury, UK) was
used for signal detection. Films were quantified using a densitometer.
Control experiments with various amounts of protein (5–50 µg) were
performed to ensure that densitrometric signal intensity was
proportional to the loaded amount of protein.
IGF1R protein expression. Confluent preadipocytes were scraped and sonicated in cold buffer containing 10 mM Tris (pH 7.4), 0.25 M sucrose, 5 mM EDTA, 0.5 mM phenylmethylsulfonylflouride, 25 µg/ml aprotinin, and 105 µM leupeptin. After centrifugation at 21,000 x g for 20 min at 4 C, the pellet was resuspended and denatured with Laemmli buffer (vol/vol) and stored at -20 C. Membrane extracts (40 µg) were resolved by SDS-PAGE (7.5% acrylamide). Proteins were transferred to polyvinylidenedifluoride membranes overnight at 4 C and blocked for 2 h, at room temperature, in buffer A with 2.5% gelatin. Primary polyclonal IGF1R antiserum (1:300 dilution) was then added in buffer A with 2.5% gelatin and incubated overnight at room temperature. Incubation with the secondary antiserum and signal detection were performed as described above. Control experiments with various amounts of protein (20–100 µg) were performed to ensure that densitrometric signal intensity was proportional to the loaded amount of protein.
Other determinations
Protein concentration was measured according to Bradford (32),
with BSA as standard. All results are expressed as means ±
SEM from at least three individual experiments. Statistical
significance was established using Student’s t test or
ANOVA test when multiple treatment groups were compared.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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These experimental conditions are similar to those demonstrating a
mitogenic effect of sex steroids in other cell types (35). Because the
proliferative capacities of preadipocytes are variable according to fat
depots (36, 37), this study was performed on male and female rat
preadipocytes from femoral sc and deep intraabdominal fat depots. Under
these experimental conditions, none of the steroids tested
(testosterone, DHT, androstanediol, androstenediol, DHEA,
DHEA-S, 17ß-estradiol, estrone), at 10 nM
concentration, had any effect on preadipocyte growth in male rats (data
not shown). However, as recent studies have demonstrated a positive
effect of estrogens on both creatine kinase B expression and leptin
secretion in female rat adipose tissue specifically (38, 39), we have
reexamined the effects of estrogens on the proliferation rate of sc and
parametrial preadipocytes removed from nonovariectomized or
ovariectomized female rats. As shown in Fig. 1
, exposure to 10 nM
17ß-estradiol resulted in a significant increase in the growth rate
of sc (x1.9) but not of parametrial preadipocytes from ovariectomized
rats (Fig. 1). Moreover, this positive effect of 17ß-estradiol was
abolished by the estrogen receptor antagonist ICI182780 (1
µM) (Fig. 1). Identical results were observed with
preadipocytes from nonovariectomized females (x2.06 and x1.17 in sc
and parametrial preadipocytes, respectively; data not shown). Thus
estrogens elicit in vitro a mitogenic response in sc
preadipocytes from female, but not from male, rats.
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The modulatory effects of androgens on the adipose conversion process
were studied in preadipocytes from male rats. As shown in Fig. 2, A and B, GPDH activity was either
markedly decreased in epididymal (-60 to -70%) or slightly reduced
in sc (-20 to -30%) preadipocytes after exposure to pharmacological
concentrations (10 µM) of testosterone or DHT. Moreover,
in epididymal preadipocytes, this antiadipogenic effect of androgens
was dose-dependent, being already significant at 10 nM DHT
concentration (30% inhibition P < 0.05) and was
almost completely reversed by simultaneous exposure to the potent
androgen receptor antagonist RU23908 (10 µM)
(Fig. 2A).
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) and ovariectomized female rats (Fig. 2D).
Exposure to 10 nM 17ß-estradiol failed to alter GPDH
activity in epididymal and sc preadipocytes from male rats. However, at
high 17ß-estradiol concentration (10 µM), a weak (but
significant) stimulating effect on GPDH activity was observed in
epididymal, but not in sc, preadipocytes. In ovariectomized females,
exposure to 10 nM 17ß-estradiol concentrations resulted
in a +30% increase in GPDH activity in parametrial, but not in sc,
preadipocytes. Higher concentrations (0.1 µM or 1
µM) of 17ß-estradiol did not further increase GPDH
activity in preadipocytes from these ovariectomized rats (not shown).
Moreover, the proadipogenic effect of 17ß-estradiol in parametrial
preadipocytes was suppressed by simultaneous exposure to the estrogen
receptor antagonist ICI 182780 (0.1 µM) (Fig. 2D).
In various cell types, regulation of growth and differentiation by
steroid hormones seems to be mediated, at least in part, through
changes in the expression of some growth factors and/or their receptors
(40, 41, 42). Among these growth factors, IGF1 is considered as an
important mitogenic and adipogenic factor (43). However, the mitogenic
potency of IGF1 seems to be variable according to the preadipocyte
anatomical origin. As a matter of fact, experiments performed with anti
IGF1 antiserum in the culture medium (4 µg/ml), during 3 days post
plating, revealed that depletion of exogenous and endogenous IGF1
results in a significantly higher decrease of cell growth in sc than in
parametrial preadipocytes (-58.5% ± 6.5 vs. -23% ± 3,
P < 0.05). These observations led us to compare the
influence of androgens and estrogens on IGF1R expression during the
early phase of differentiation (4 days culture) in preadipocytes from
different anatomical origins. As shown in Fig. 3, exposure to DHT (10
nM) resulted in a significant decrease (-40%)
in IGF1R expression in epididymal preadipocytes. This effect was
prevented by simultaneous exposure to RU23908 (10
mM). In contrast, in male rat sc preadipocytes,
IGF1R expression was not modified by DHT exposure (Fig. 3). Next, IGF1R
expression was compared, under the same conditions as above, in
preadipocytes from nonovariectomized and ovariectomized female rats. As
shown in Fig. 4, ovariectomy induced a
significant decrease (-60%) in IGF1R expression. Now when
preadipocytes from ovariectomized rats were exposed in vitro
to 17ß-estradiol (10 nM), a significant
increase in IGF1R expression was observed in sc preadipocytes (+75%)
but not in parametrial preadipocytes (not shown). As also depicted in
Fig. 5, these effects of estrogens were
abolished by the estrogen receptor antagonist ICI182780 (0.1
µM).
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2, that
activates the expression of adipose specific genes such as aP2,
adipsine, and LPL during adipogenesis (for review, see Ref. 6) led us
to investigate the influence of sex hormones on PPAR2 expression. By
immunoblotting, we have first established that PPAR2 is present in
confluent preadipocytes; and, in agreement with previous reports on
preadipocyte cell lines, we have confirmed that the PPAR2 expression
is maintained at a constant level throughout the differentiation
process in control cells.
As shown in Fig. 6, PPAR2 protein
expression in differentiated cells was much lower (-60%) in sc than
in epididymal preadipocytes from male rats. Moreover, 2-bromo
palmitate, an adipogenic factor (44), increased PPAR2 expression in
both epididymal and sc preadipocytes (x 1.74 ± 0.22 and x
2.11 ± 0.33) and the GPDH activity in epididymal specifically (x
5.5 ± 1.56 vs. x 1.13 ± 1.05). Testosterone and
DHT had no effect on PPAR2 expression, but 17ß-estradiol increased
PPAR2 expression in epididymal preadipocytes and in parametrial
preadipocytes from ovariectomized rats.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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After exposure to estrogens, we have found over 2-fold increase in proliferation rate in sc preadipocytes from female rats only. This effect was mediated by estrogen receptors, because, in the presence of ICI182780, the positive effect of estrogens was completely abolished. These results are consistent with previous investigations carried out in human sc preadipocytes (14).
Recent studies have reported that estrogens in mammary tumors (40) and androgens in prostatic cell lines (41) modulate cell proliferation by up-regulating EGF receptor and IGF1R expression. EGF does not significantly affect rat preadipocyte growth (45), whereas IGF1 is a potent mitogenic factor for these cells (43). These findings led us to examine the influence of estrogens on IGF1R expression in female rat preadipocytes. In confluent sc preadipocytes, a positive effect of 17ß-estradiol on IGF1R expression was, in fact, observed, which could well contribute to explaining the mitogenic action of estrogens observed in these cells. Moreover, in the presence of the antiestrogen ICI182780, this effect of 17ß-estradiol was completely blocked. This result suggests that the estrogen receptors, identified in rat confluent sc preadipocytes (46), are involved in the IGF1R up-regulation by estrogens. Further experiments are currently in progress, to determine whether estrogens (via these receptors) are modulators of the IGF1R phosphorylation/dephosphorylation balance that is crucial for the signaling activity of this receptor (43).
Under our experimental conditions, the different androgens (testosterone, DHT, DHEA(S), androstanediol, and androstenediol) tested at rather low concentration (i.e. 10 nM) failed to affect preadipocyte proliferation in male rats. This contrasts with other studies showing that DHEA concentrations in the micromolar range induce antimitogenic effects in 3T3-L1 cells or in stromal adipose precursor cells from rat and pig (18, 19).
The present experiments demonstrate that testosterone acts as a negative effector of terminal differentiation of rat preadipocytes. Identical results were obtained with DHT (the nonaromatizable testosterone metabolite), suggesting the androgen specificity of these testosterone effects. Moreover, the potent androgen antagonist RU23908 (47) reversed (almost completely) the negative action of DHT on GPDH activity. This result suggests that the antiadipogenic effects of androgens seem, at least in part, to be androgen receptor dependent. Adding further weight to this suggestion is our recent finding that androgen receptors are expressed at high level during the first days of adipogenesis (22). In contrast, sc adipose precursor cells seem less sensitive to the antiadipogenic effect of androgens, in comparison with epididymal cells. This difference seems also to be explained by the site-specificity of androgen receptor expression, because androgen receptor density is about two times lower in sc than in epididymal preadipocytes (22).
One mechanism that could explain the antiadipogenic effect of androgens
is a reduced transcription of genes encoding adipogenic transcriptional
factors. Among these factors, PPAR2 which is considered as one of
the master regulator genes of the adipoconversion process could be a
target of androgens for the following reasons: 1) the PPAR gene
regulatory unit includes various hormone responsive elements (48)
including a GRE which is a DNA binding domain for glucocorticoid
receptors but also for androgen receptors (49); and 2) two recent
studies reported that the glucocorticoid, dexamethasone, strongly
increases the expression of PPAR2 in 3T3 fibroblasts (50) and of
another member of the PPAR family, PPAR , in hepatic cells (48). In
the present study, however, we were unable to observe a negative
regulation of PPAR2 expression by androgens. Therefore, other
mechanisms have to be considered to explain the antiadipogenic action
of androgens.
IGF1 is an essential regulator of the adipose conversion process; although, in 3T3-L1 preadipocytes, IGF1R expression remains constant throughout the differentiation phase (51). In this study, exposure of epididymal precursor cells to androgens was found to decrease the IGF1R expression apparently through an androgen receptor-dependent mechanism as well. This limitation in the IGF1 signaling pathway, caused by androgens at the receptor level, may partly explain how androgens reduce adipose tissue development in deep fat deposits.
High blood levels of the androgen precursors DHEA and
DHEA-S have been reported in abdominal obesity (52),
suggesting a possible role of DHEA and DHEA-S
in adipose tissue development. DHEA (but not
DHEA-S) was reported to clearly inhibit adipose conversion
in 3T3-L1 and F442A cell lines (17, 19) and in pig or rat preadipocytes
(18). One mechanism put forward to explain how DHEA
reduces the differentiation of 3T3 fibroblasts into adipocytes is: a
reduced fatty acid synthesis caused by DHEA inhibition of
glucose-6-phosphate dehydrogenase activity (17). However, this
mechanism seems to be excluded from explaining the negative effect of
androgens on rat preadipocytes, because, in 3T3 fibroblasts,
testosterone and DHT block adipose conversion without changing
glucose-6-phosphate dehydrogenase activity (17). Another mechanism that
has been proposed to explain the antiadipogenic effect of
DHEA is: a reduced C/EBP expression (18). Our
preliminary experiments, however, failed to reveal any significant
variations in C/EBP and C/EBPß expressions after exposure to DHT
and testosterone in preadipocytes undergoing differentiation. Thus, the
precise molecular mechanism of the antiadipogenic effect of androgens
remains to be determined.
Involvement of estrogens in the regulation of adipogenesis is
poorly described in the literature (16). Therefore, we have also
investigated the possible influence of estrogens on the adipoconversion
process. In contrast to androgens, 17ß-estradiol increased GPDH
activity, an effect apparently gender dependent, because it was
restricted to parametrial and, only at pharmacological concentrations,
to epididymal preadipocytes. Although unestablished, the mechanisms
explaining this gender-specific action of estrogens could involve
differences in the expression of estrogen receptor subtypes ( and
ß) and of nuclear receptor cofactors between preadipocytes from male
and female. In fact, these nuclear receptors regulate the
transcriptional activity of specific genes by recruiting an array of
coactivator proteins, including SRC1 (steroid receptor coactivator 1),
whose expression was recently reported to be sex specific (53). Whether
this site specificity and the gender dependency of the proadipogenic
action of estrogens reported in this study may explain the changes in
adipose tissue distribution and development occurring in females at
puberty during pregnancy (1) and after chronic hormonal therapy (54)
remains to be established.
In opposition to androgens, however, the promoting action of estrogens
on adipose conversion in vitro does not seem related to
changes in IGF1R expression, because, in parametrial preadipocytes,
where estrogens enhance the adipose conversion process, estrogens do
not alter IGF1R expression. Conversely, our experiments showed that, in
sc preadipocytes, estrogens enhanced IGF1R expression but had no
influence on the adipose conversion process. This site specificity of
estrogen action on adipogenesis is in agreement with earlier reports
showing that ovarian factors, in vivo, promote regional
specialization in the development of adipose tissue depots (55).
Interestingly, the proadipogenic action of estrogens on parametrial
preadipocytes is accompanied by an increase in PPAR2 expression in
ovariectomized rats. Finally, chronic exposure of rat preadipocytes to
estrogens during the differentiation phase failed to alter the
expression of C/EBP and C/EBPß, as did exposure to androgens
(preliminary experiments). These negative results do not allow
exclusion of the possibility that the opposite effects of androgens and
estrogens on adipose differentiation process are independent of any of
these transcriptional factors. In fact, the possibility that sex
steroids modify the DNA binding activity of some of these factors
cannot be ruled out. If so, androgens and estrogens, via their specific
nuclear receptors, would act as modulators of the adipogenic
transcriptional activity of PPAR 2 and the members of the C/EBP
family. Consistent with this hypothesis is the recent discovery that
ARA70, a specific coactivator of androgen receptors, is able to enhance
the transcriptional activity of PPAR2 in adipocytes, which strongly
suggests that, in these cells, a cross-talk occurs between PPAR2 and
the androgen receptor-mediated responses (56). Sex steroids could also
modulate biosynthesis of ligands for these adipogenic transcriptional
factors. Indeed, estrogens were recently reported to promote the
production of a PPAR ligand, PGJ2, in a PPAR1-expressing tissue,
leading to overexpression of PPAR1 (57). Further investigations are
currently in progress to test these different hypotheses.
In conclusion, the present study shows that androgens and estrogens are
able to modulate, in vitro, the adipose conversion of rat
preadipocytes. On the whole, androgens elicit antiadipogenic effects
contrary to estrogens that behave as proadipogenic factors; and the
modulation of the differentiation process by sex steroids is more
pronounced in preadipocytes from deep, rather than superficial, fat
depots. The present study also suggests that estrogens and androgens
exert their modulatory effects on preadipocyte terminal differentiation
via their own receptors acting as regulators of the IGF1R and PPAR2
expression.
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Footnotes |
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Received June 11, 1999.
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R. Okazaki, D. Inoue, M. Shibata, M. Saika, S. Kido, H. Ooka, H. Tomiyama, Y. Sakamoto, and T. Matsumoto Estrogen Promotes Early Osteoblast Differentiation and Inhibits Adipocyte Differentiation in Mouse Bone Marrow Stromal Cell Lines that Express Estrogen Receptor (ER) {alpha} or {beta} Endocrinology, June 1, 2002; 143(6): 2349 - 2356. [Abstract] [Full Text] [PDF]
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 F. Machinal-Quelin, M. N. Dieudonne, M. C. Leneveu, R. Pecquery, and Y. Giudicelli Proadipogenic effect of leptin on rat preadipocytes in vitro: activation of MAPK and STAT3 signaling pathways Am J Physiol Cell Physiol, April 1, 2002; 282(4): C853 - C863. [Abstract] [Full Text] [PDF]
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G. Guercio, M. A. Rivarola, E. Chaler, M. Maceiras, and A. Belgorosky Relationship between the GH/IGF-I Axis, Insulin Sensitivity, and Adrenal Androgens in Normal Prepubertal and Pubertal Boys J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1162 - 1169. [Abstract] [Full Text] [PDF]
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L. A. Anderson, P. G. McTernan, A. H. Barnett, and S. Kumar The Effects of Androgens and Estrogens on Preadipocyte Proliferation in Human Adipose Tissue: Influence of Gender and Site J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 5045 - 5051. [Abstract] [Full Text] [PDF]
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G. Fruhbeck, J. Gomez-Ambrosi, F. J. Muruzabal, and M. A. Burrell The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation Am J Physiol Endocrinol Metab, June 1, 2001; 280(6): E827 - E847. [Abstract] [Full Text] [PDF]
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