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Blocks Adipocyte Differentiation But Does Not Revert the Phenotype of Terminally Differentiated Adipocytes
Department of Cell Biology and Endocrinology, Pfizer Global Research and Development (H.S.C., A.C., T.L.), and Department of Biological Chemistry, University of Michigan Medical School (T.L.), Ann Arbor, Michigan 48105
Address all correspondence and requests for reprints to: Heidi S. Camp, Department of Cell Biology and Endocrinology, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105. E-mail: Heidi.Camp{at}pfizer.com
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(PPAR). Their antihyperglycemic effects seem to be linked to the
regulation of PPAR-responsive genes. Here, we report the
characterization of a specific PPAR antagonist that blocks several
of the biological activities of the PPAR agonist rosiglitazone.
PD068235 inhibited rosiglitazone-dependent PPAR transcriptional
activity with an IC50 of 0.8 µM and
rosiglitazone-stimulated in vitro coactivator
association. The role of PPAR in the initiation of differentiation
is well documented. In this study, we used PD068235 as a tool to
evaluate the functional role of PPAR in the maintenance of the
terminally differentiated state. Treatment of confluent,
growth-arrested 3T3-L1 preadipocytes with PD068235 blocked adipocyte
differentiation induced by the standard adipogenic hormonal mixture
(insulin/dexamethasone/isobutylmethylxanthin) and fully antagonized
rosiglitazone-induced adipogenesis. In contrast, long-term treatment of
terminally differentiated 3T3-L1 adipocytes with PD068235 did not
induce any obvious morphological changes and had no effect on basal
lipolysis rates. In addition, in fully differentiated adipocytes
PD068235 did not alter the basal expression of PPAR target genes aP2
and CAP, but it effectively blocked rosiglitazone-induced expression of
both genes. These results suggest that in terminally differentiated
adipocytes, the PPAR activity is minimal and may not be required for
the maintenance of PPAR target gene expression. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, , and 
) that differ in their tissue distribution
and ligand specificity (2, 3, 4). PPAR, the expression of
which is highly enriched in adipose, plays a key role in adipocyte
differentiation (5, 6). These results were substantiated
by recent reports describing the total lack of adipose tissue formation
in PPAR null mice (7, 8).
In addition to its role in adipogenesis, PPAR seems to be an
important transcriptional regulator of genes involved in glucose and
lipid metabolism. A critical role for PPAR in metabolic regulation
was first demonstrated by the observation that the antidiabetic drugs
known as thiazolidinediones (TZDs) are high-affinity ligands of
PPAR (9). TZDs improve peripheral insulin sensitivity,
leading to reduced blood glucose and insulin levels in type II diabetic
patients (10, 11, 12, 13). It has been reported that the rank
order of receptor affinity of these compounds correlates with their
in vivo hypoglycemic activity (9), with a few
exceptions (14, 15). However, the mechanism by which
regulation of PPAR leads to improvement of insulin sensitivity is
unclear. This lack of understanding is underscored by two independent
recent reports that heterozygous PPAR-deficient mice are more
insulin sensitive compared with the wild-type mice (16, 17). In contrast, however, Barroso et al.
(18) recently identified a loss-of-function mutation in
the human PPAR gene that is associated with severe insulin
resistance. The availability of a specific PPAR antagonist would be
a useful tool to further characterize the role of PPAR in regulating
insulin sensitivity. Here, we report the characterization of a specific
and potent PPAR antagonist that arrests adipocyte differentiation at
an early stage, but does not revert the phenotype of terminally
differentiated adipocytes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF) was purchased from Genzyme (Cambridge,
MA). [3H] BRL 49653 (60 Ci/mmol)
was purchased from American Radiolabeled Chemicals, Inc. (St. Louis,
MO).
Ligand displacement assay
The ligand-binding domain (LBD) of human PPAR (amino
acids 175–476) was cloned into the Escherichia coli
expression vector GST-5X (Amersham Pharmacia Biotech,
Uppsala, Sweden). The resulting
glutathione-S-transferase (GST)-PPAR LBD fusion
protein was expressed, isolated, and partially purified using
glutathione agarose. The binding assay was carried out in a buffer
containing 25 mM KCl, 10 mM
DTT, 20 mM Tris-HCl (pH 7.5), 5% DMSO, 0.01%
Triton X-100, and 10 nM BRL 49653
[3H] (60 Ci/mmol) in a final volume of 100
µl. The binding reaction was performed in a 96-well filter plate at
room temperature for 2 h in the presence of approximately 10 µg
of immobilized GST-PPAR LBD fusion protein. The plates were
filtered, washed, and counted for radioactivity in a 1450 Microbeta
Plus liquid scintillation counter (Wallac, Inc.,
Gaithersburg, MD).
Cell culture
3T3-L1 preadipocytes were cultured and induced to differentiate
as described (19). Briefly, 2 days postconfluent
preadipocytes were treated with 0.25 µM dexamethasone,
0.5 mM IBMX, and 1 µg/ml insulin for 2 days in 10% FBS
containing DMEM. Cells were then switched to 10% FBS/DMEM media
containing only insulin for 2 additional days, and then changed to 10%
FBS/DMEM without insulin. In some cases, PPAR antagonist PD068235
was added to the media at the beginning of differentiation together
with either rosiglitazone (1 µM), or the
dexamethasone/IBMX/insulin mixture. Medium was replenished with
appropriate ligands and hormones every 2 days. In some cases, cells
were first differentiated into adipocytes using the standard
differentiation protocol and then treated with ligands as indicated for
24 h to 4 days. The level of lipid content was determined by
staining the cells with Oil Red O.
Brown adipocyte progenitors were isolated from interscapular brown
adipose tissue of FVB/N1 mice (Taconic, Germantown, NY) as described
previously (20). Isolated precursor cells were
seeded at a density of 104
cells/mm2 in DME supplemented with 10% FBS and
grown at 37 C in an atmosphere of 10% CO2 in
air. The media were changed 1 day after plating and changed every 2
days thereafter. On reaching confluence, cells were exposed to the
following composition: 50% DME, 50% Ham’s F12 medium, 10% FBS, 16
µM biotin, 18 µM pantothenic acid, 2
mM glutamine, 15 mM HEPES, 50 IU/ml penicillin,
50 µg/ml streptomycin, 100 µM ascorbate, 10 µg/ml
transferrin, 510 nM insulin, 100 nM
dexamethasone, 1 µM rosiglitazone, and 0.2 nM
3,3',5-triiodo-L-thyronine. Progenitors differentiated into
brown adipocytes 5–7 days after the addition of differentiation media.
At this time, cells were switched to DME/Ham’s F12 media containing
10% FBS. After 1 day, adipocytes were exposed to either 30
µM PD068235 or 0.5 nM TNF for 4 days.
Cells were stained with Oil Red O to determine lipid content.
Transient reporter assays
The reporter construct used in the native receptor
reporter assay (ARE6.3XTKpGL3) contained three copies of the PPRE site
(ARE6) from the aP2 enhancer (21) inserted upstream of the
minimal thymidine kinase promoter in the pGL3 luciferase vector
(Promega Corp., Madison, WI). C2C12 cells were grown in
10% FBS/DMEM and plated into 24-well plates at 50% confluence. The
cells were transfected with expression plasmids encoding mouse PPAR1
(200 ng), mouse RXR (50 ng), the ARE6.3XTKpGL3 (200 ng), and the
internal reference plasmid pCMV ß-galactosidase (50 ng) using
lipofectamine (Life Technologies, Inc., Gaithersburg, MD).
After transfection, cells were treated for 48 h with the indicated
ligands. Luciferase and ß-galactosidase activities were determined
using the Dual-Light luciferase and ß-galactosidase reporter gene
assay system (Tropix, Inc., Bedford, MA).
The chimeric receptor plasmids pTetmPPAR-LBD, pTetmPPAR-LBD, and
pTetmPPAR-LBD were constructed by fusing LBDs of mouse PPAR1
(amino acids 175–476), PPAR (amino acids 226–469), or PPAR
(amino acids 127–441) to the DNA-binding domain of the E.
coli tetracycline (tet) repressor (amino acids 1–214).
The luciferase reporter plasmid pLTetP was constructed by cloning the
tet repressor binding site
(HindIII-XhoI fragment) from pTET-tTAK
(Life Technologies, Inc.) upstream of the
luciferase coding region of pGL3-basic (Promega Corp.).
Transfection of the human kidney epithelial cell line 293T was carried
out by electroporation using the Cell Porator system from Life Technologies, Inc. according to the manufacturer’s
instructions. After transfection, cells were plated onto 96-well plates
and treated immediately with ligands as indicated. In 3T3-L1
transcription assay, fully differentiated adipocytes were transfected
with FATP3X.TKpGL3 reporter plasmid using the electroporation method as
described previously (22).
In vitro coactivator binding assay
Full-length human SRC-1was labeled with
[35S]-methionine in a coupled in
vitro transcription-translation system (Promega Corp.). The coactivator binding assay was carried out
essentially as described (23). Briefly, 3–5 µl
[35S]-methionine SRC-1 was incubated with
immobilized GST-PPAR LBD in GST-binding buffer [50
mM KCl, 20 mM HEPES (pH
7.9), 2 mM EDTA, 0.1% Nonidet P-40, 10%
glycerol, 0.5% nonfat dry milk, 5 mM DTT, and
standard protease inhibitors], together with appropriate ligands. The
mixture was incubated for 2 h with gentle rocking at 4 C. The
beads were washed four times with 1 ml GST-binding buffer containing
150 mM NaCl. The bound proteins were eluted in 20
µl 2x SDS loading buffer, run on 10% SDS-polyacrylamide gels, and
visualized by autoradiography.
Analysis of RNA
Total cellular RNA was isolated from 3T3-L1 cells using the
Ultraspec RNA isolation system (Biotecx Laboratories, Inc., Houston,
TX). Northern blot analysis was performed with approximately 15 µg
total RNA using mouse aP2 and rat ß-actin complementary DNA (cDNA)
probes. RNase protection assays were performed using the RPA II
ribonuclease protection assay kit (Ambion, Inc., Austin,
TX). The antisense [-32P] UTP-labeled
single-stranded RNA probe for CAP has been described previously
(24).
Lipolysis
Fully differentiated adipocytes were equilibrated with 500 µl
2%BSA/DMEM for 24 h. Cells were then treated with indicated
reagents for 48 h, and then the media were harvested. Lipolysis
was monitored as the amount of glycerol released into the media.
Glycerol was measured by a coupled enzymatic assay as described
previously (25).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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antagonist
) was initially
identified in a screen for compounds that interacted with the PPAR
receptor. To measure the affinity of PD068235 for PPAR, a ligand
displacement assay was performed using partially purified recombinant
GST-PPAR LBD protein incubated with a fixed amount of
[3H] rosiglitazone and increasing
concentrations of PD068235. In this assay, PD068235 displaced
rosiglitazone with a Ki of 0.84 µM
(Fig. 1B).
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transcriptional activity, C2C12 myoblast cells were cotransfected with
full-length mouse PPAR1 and RXR cDNA, and a reporter plasmid
containing a triple copy of a PPAR response element from the mouse aP2
gene enhancer (ARE6.3XTKpGL3). PD068235 itself did not cause any
significant change in PPAR transcriptional activity (data not
shown). However, cotreatment with 8 µM rosiglitazone, a
PPAR agonist, and increasing concentrations of PD068235 resulted in
a dose-dependent decrease in rosiglitazone-stimulated PPAR
transcriptional activity, with an IC50 of 0.82
µM (Fig. 2A).
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, PPAR, or
PPAR was fused to the bacterial tetracycline repressor DNA-binding
domain. Plasmids producing these receptors were cotransfected into 293T
cells with a reporter plasmid containing the tet repressor
binding site driving expression of the luciferase gene. Transfected
cells were treated with appropriate ligands: rosiglitazone (), Wy
14643 (), or L-165041 () in the presence or
absence of PD068235. PD068235 alone did not stimulate the
transcriptional activity of any of the PPAR isoforms (data not shown).
However, PD068235 decreased ligand-stimulated PPAR transcriptional
activity with an IC50 of 0.7
µM (Fig. 2B
), but failed to reduce the
ligand-mediated PPAR or PPAR transcriptional activity. These
results indicate that PD068235 is specific for the PPAR isoform.
Recruitment of the coactivator SRC-1 to agonist-bound receptor is
inhibited by PD068235
As demonstrated in studies on steroid hormone receptors that one
of the immediate effects of agonist binding to receptors is the
recruitment of transcriptional coactivators via helix 12 of the
receptor, which constitutes the ligand-dependent AF-2 transactivation
domain (26). Conversely, antagonists block coactivator
binding by disrupting the topography of the AF-2 surface, inducing a
conformation that is distinct from the agonist-induced conformation
(27). To determine whether PD068235 can prevent the
agonist induced coactivator association, an in vitro PPAR
pull-down assay was performed with SRC-1. The addition of rosiglitazone
to the mixture containing the GST-PPAR LBD fusion protein and
[35S]-Met labeled full-length SRC-1 resulted in
a dosedependent increase in SRC-1 association to the receptor
(Fig. 3A). Coincubation of rosiglitazone
(1.0 µM) with increasing concentrations of
PD068235 led to dose-dependent decrease in the recruitment of SRC-1 to
the receptor (Fig. 3B). In contrast, the association of SRC-1 to
liganded PPAR was not affected by PD068235, indicating that
the inhibition of rosiglitazone-induced SRC-1/PPAR association was
not a nonspecific effect (Fig. 3C).
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). Cotreatment of cells with PD068235
and rosiglitazone resulted in a complete inhibition of
rosiglitazone-induced aP2 expression. These results indicate that
PD068235 antagonizes rosiglitazone-stimulated in vitro
adipocyte differentiation.
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, treatment with PD068235
inhibited hormone-induced adipogenesis in a dose-dependent
manner.
PPAR expression is dramatically up-regulated during early days (1–2
days of postdifferentiation) of the adipocyte differentiation program
(1, 5), suggesting that the level of the endogenous
PPAR ligand is also high at this time. To determine the importance
of PPAR activation at different stages of adipocyte differentiation,
3T3-L1 preadipocytes were treated with the standard adipogenic mixture
and then with PD068235 at either 0, 1, or 2 days after the initiation
of differentiation process. Total RNA was isolated on day 3, and the
level of aP2 mRNA expression was examined. As expected, the aP2 mRNA
level was significantly reduced by PD068235 when added in the beginning
of differentiation process (Fig. 4C). The effect of PD068235 on aP2
mRNA expression, however, was less pronounced when added on day 1 and
had no effect when added on day 2. These results suggest that the
activity of PPAR is crucial for differentiation only at very early
stages.
Effects of PD068235 on fully differentiated adipocytes
Although PPAR clearly plays an important function in the
initiation stage of adipogenesis, its role in the maintenance of
adipocyte morphology, hormone sensitivity and target gene expression in
terminally differentiated adipocytes is unclear. To determine whether
PPAR activity is required for the maintenance of adipocyte
morphology, fully differentiated 3T3-L1 adipocytes were treated with
increasing concentrations of PD068235 or with TNF for 4 days. Cells
were then stained with Oil Red O to visualize the lipid content. As
shown in Fig. 5A, PD068235-treated cells
showed no obvious morphological changes in cell shape or lipid content.
In contrast, TNF treatment caused the dedifferentiation of
adipocytes. Cotreatment with PD068235 and TNF did not further
increase the dedifferentiation process (data not shown). We also
cultured mouse brown adipocyte progenitor cells, differentiated into
brown adipocytes, and treated with PD068235 for 4 days. Again, PD068235
did not have any significant effect on the morphology of the cells,
whereas TNF clearly induced the dedifferentiation process as
indicated by the reduced lipid content of adipocytes (Fig. 5B).
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increases lipolysis in 3T3-L1
adipocytes and that TZDs can partially reverse this effect
(30). To determine whether PD068235 can antagonize the
inhibitory effect of rosiglitazone on TNF-stimulated lipolysis,
fully differentiated 3T3-L1 adipocytes were treated with either TNF
alone or increasing concentrations of rosiglitazone in the presence or
absence of PD068235. PD068235 alone had no effect on TNF induced
lipolysis (data not shown), whereas rosiglitazone inhibited
TNF-induced lipolysis in a dose-dependent manner (Fig. 6A). However, cotreatment with PD068235
antagonized the effect of rosiglitazone as shown by the rightward shift
of the rosiglitazone dose-response curve.
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in 3T3-L1 cells, fully differentiated adipocytes were
transfected with a PPRE containing reporter plasmid and treated with
increasing concentration of rosiglitazone in the presence or absence of
PD068235. As shown in Fig. 6B, 1 µM PD068235 resulted in
a rightward shift of the rosiglitazone dose-response curve. In
addition, cotreatment with rosiglitazone and increasing concentrations
of PD068235 resulted in a dose-dependent decrease in
rosiglitazone-induced PPAR transcriptional activity (data not
shown).
To further characterize the effect of PD068235 in fully differentiated
adipocytes, we examined the effect of this compound on the expression
of known PPAR target genes. Fully differentiated 3T3-L1 adipocytes
were treated with either DMSO alone, or with increasing concentrations
of rosiglitazone in the presence or absence of PD068235 for 24 h.
Total RNA was isolated and the aP2 and CAP mRNA levels were determined
(Fig. 7). The basal expression level of
aP2 and CAP did not change with the PD068235 treatment. This is
consistent with the experiments showing that PD068235 had no effect on
cellular morphology or lipolysis in fully differentiated adipocytes.
However, RNA samples derived from rosiglitazone-treated cells showed a
dose-dependent increase in both aP2 and CAP expression that was
significantly inhibited by PD068235 (Fig. 7). Taken together, these
results strongly suggest that in terminally differentiated adipocytes,
the PPAR activity is minimal, and is not required for the
maintenance of PPAR target gene expression.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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antagonist
that blocks the ability of rosiglitazone to activate transcription, to
recruit coactivators in vitro, and to induce adipocyte
differentiation. In addition, this compound, PD068235, blocks fat cell
formation induced by the standard adipogenic hormonal mixture
confirming that the activity of PPAR is absolutely required for
adipogenesis. Our results are in agreement with the recent report
describing the antiadipogenic effect of a PPAR antagonist Bisphenol
A diglycidyl ether (31). We speculate that the
concentration of the bona fide endogenous PPAR ligand is relatively
high at the beginning of differentiation (day 0 to day 2), and this
activity can be inhibited by PD068235 when added at the initiation of
the adipogenesis, as indicated in Fig. 4C. The inhibitory effect of
PD068235 on differentiation was lost 2 days after differentiation,
suggesting that the cells of this stage have already committed to
differentiation and that they do not require PPAR activity to
continue the process.
The contribution of PPAR to the maintenance of adipocyte
phenotype is unknown, although it has been suggested that its
expression is necessary for the maintenance of the adipocyte phenotype
(32). This conclusion was based on the observation that
TNF, an antiadipogenic factor, decreased the level of PPAR
expression and that the antiadipogenic effect of TNF was attenuated
by overexpressing PPAR. Antisense or dominant negative approaches
have been largely unsuccessful due to difficulty of delivery system in
adipocytes. The availability of potent PPAR antagonist, therefore,
provides a means to study the role of PPAR in the physiology of
fully differentiated adipocytes. In our current study, we find that the
direct inhibition of endogenous PPAR activity by PD068235 does not
effect the morphology, basal lipolysis status, or basal expression of
PPAR target genes in fully differentiated 3T3-L1 adipocytes. This
lack of effect is not due to an inability of PD068235 to act as an
antagonist of PPAR in this cell system, because it is quite
effective in inhibiting rosiglitazone-stimulated PPAR activity.
A possible explanation for the lack of effect of PD068235 in
adipocytes is that the affinity of PD068235 for the receptor is much
lower than the affinity of the endogenous real PPAR ligand, making
it unable to compete effectively for PPAR binding. This scenario is
unlikely because we have shown that PD068235 can block PPAR
activation during early stage of fat cell differentiation induced by
the standard adipogenic mixture, presumably by antagonizing the
activity of an endogenous PPAR ligand. An alternative explanation is
that PPAR is not active in fully differentiated adipocytes, perhaps
because of low endogenous PPAR ligand concentration. We have
previously observed that while PPAR protein levels increase
dramatically in the first 2 days of differentiation, they decline
significantly in the later stages of adipogenesis (33).
The lack of effect of the antagonist in fully differentiated adipocytes
may, therefore, be due to a combination of reduced PPAR levels and
low endogenous ligand concentration. Taken together, our results
support a model in which PPAR plays a minor role in the maintenance
of the fully differentiated state of adipocytes. In terminally
differentiated cells, C/EBP, the expression of which rises
during the later stages of adipogenesis, may have a more important
function in the maintenance of adipocyte phenotype. C/EBP transcription
factors are known to regulate many adipocyte-enriched genes such as aP2
and CAP, and it may be more important than PPAR in the expression of
these genes in terminally differentiated cells.
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Acknowledgments |
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fusion protein, Vered Ribon for CAP cDNA, and Alan
Saltiel and Matt Brady for valuable discussion and for reading the
manuscript. Received October 13, 2000.
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References |
|---|
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2: tissue-specific regulator of an
adipocyte enhancer. Genes Dev 8:1224–1234 and promotes adipocyte
differentiation. Cell 83:813–819[CrossRef][Medline]
2, a
lipid-activated transcription factor. Cell 79:1147–1156[CrossRef][Medline]
. Curr Opin Genet Dev 5:571–576[CrossRef][Medline]
is required
for the differentiation of adipose tissue in vivo and
in vitro. Mol Cell 4:611–617[CrossRef][Medline]
is required for
placental, cardiac, and adipose tissue development. Mol Cell 4:585–595[CrossRef][Medline]
agonism and the antihyperglycemic
activity of thiazolidinediones. J Med Chem 39:665–668[CrossRef][Medline]
-activating
properties. J Biol Chem 273:32679–32684
activator, exhibits potent antidiabetic effects and induces uncoupling
protein 1 in white adipose tissue of KKAy obese mice. Diabetes 49:759–767[Abstract]
mediates high-fat diet-induced adipocyte hypertrophy and insulin
resistance. Mol Cell 4:597–609[CrossRef][Medline]
deficiency. J Clin Invest 105:287–292[Medline]
associated with severe insulin resistance, diabetes mellitus and
hypertension. Nature 402:880–883[Medline]
by troglitazone and rosiglitazone.
Diabetes 49:539–547[Abstract]
activation stimulates expression of the CAP
gene. Proc Natl Acad Sci USA 95:14751–14756 on differentiation, insulin-stimulated
glucose uptake, and gene expression in 3T3–L1 cells. Endocrinology 136:1474–1481[Abstract]
. Mol Endocrinol 10:1457–1466
activators down-regulate the expression of PPAR in 3T3–L1
adipocytes. FEBS Lett 447:186–190[CrossRef][Medline]
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 J. Rieusset, F. Touri, L. Michalik, P. Escher, B. Desvergne, E. Niesor, and W. Wahli A New Selective Peroxisome Proliferator-Activated Receptor {gamma} Antagonist with Antiobesity and Antidiabetic Activity Mol. Endocrinol., November 1, 2002; 16(11): 2628 - 2644. [Abstract] [Full Text] [PDF]
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 Y. Tamori, J. Masugi, N. Nishino, and M. Kasuga Role of Peroxisome Proliferator-Activated Receptor-{gamma} in Maintenance of the Characteristics of Mature 3T3-L1 Adipocytes Diabetes, July 1, 2002; 51(7): 2045 - 2055. [Abstract] [Full Text] [PDF]
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G. Lee, F. Elwood, J. McNally, J. Weiszmann, M. Lindstrom, K. Amaral, M. Nakamura, S. Miao, P. Cao, R. M. Learned, et al. T0070907, a Selective Ligand for Peroxisome Proliferator-activated Receptor gamma , Functions as an Antagonist of Biochemical and Cellular Activities J. Biol. Chem., May 24, 2002; 277(22): 19649 - 19657. [Abstract] [Full Text] [PDF]
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T. Albrektsen, K. S. Frederiksen, W. E. Holmes, E. Boel, K. Taylor, and J. Fleckner Novel Genes Regulated by the Insulin Sensitizer Rosiglitazone During Adipocyte Differentiation Diabetes, April 1, 2002; 51(4): 1042 - 1051. [Abstract] [Full Text] [PDF]
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 S. M. Rangwala and M. A. Lazar The Dawn of the SPPARMs? Sci. Signal., February 26, 2002; 2002(121): pe9 - pe9. [Abstract] [Full Text] [PDF]
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D. Ren, T. N. Collingwood, E. J. Rebar, A. P. Wolffe, and H. S. Camp PPARgamma knockdown by engineered transcription factors: exogenous PPARgamma 2 but not PPARgamma 1 reactivates adipogenesis Genes & Dev., January 1, 2002; 16(1): 27 - 32. [Abstract] [Full Text] [PDF]
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