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(Received for publication, July 16, 1995; and in revised form, September 7, 1995) From the
Fatty acids and thiazolidinediones act as potent activators of
the adipose differentiation program in established preadipose cell
lines. In this report, the effects of these agents on the
differentiation pathway of myoblasts have been investigated. Exposure
of C2C12N myoblasts (a subclone of the C2C12 cell line) to
thiazolidinediones or fatty acids prevents the expression of myogenin,
Formation of muscle, bone, and adipose tissue are multistep
processes that include the determination of a common progenitor
mesodermal cell toward a specific differentiation pathway followed by
the expression of various terminal differentiation phenotypes. The
multipotentiality of progenitor mesodermal cells has been illustrated in vitro by the spontaneous and concomitant differentiation of
embryonal carcinoma cells (1) or of clonal cell populations
derived from fetal rat calvaria (2) into myotubes, adipocytes,
and chondrocytes. Multiple differentiated phenotypes can also be
chemically induced by 5-azacytidine treatment of fibroblasts, such as
C3H10T1/2 or Swiss 3T3 cells(3) . Several lines of evidence
indicate that exogenous regulatory factors play a crucial role in the
determination of common progenitor cell into specific differentiation
lineages. Glucocorticoids exert positive effects on the differentiation
of the RCJ 3.1 clonal line from fetal rat calvaria into myotubes,
adipocytes, and chondrocytes(2) , whereas transforming growth
factor- In this study, we investigated the
effects of fatty acids and thiazolidinediones, on the differentiation
pathway of C2C12N myogenic cells and satellite cells from newborn mouse
muscle. We report that these compounds prevent myotube formation and
induce the expression of a new phenotype resembling that of adipose
cells.
Figure 1:
Effects of BRL 49653 on C2C12N
morphological differentiation. Cells were maintained to day 5
post-confluence in standard medium without additions (A) or in
the presence of 5 µM BRL 49653 added at confluence (B) or 2 days before confluence (C). Bars,
0.1 mm.
Figure 2:
Effects of various thiazolidinediones and
fatty acids on muscle and adipose-like differentiation of C2C12N cells.
MCK and GPDH activities were determined in 5 day post-confluent cells
maintained in standard medium (a) or exposed from day -2
to day +5 relative to confluence to 5 µM BRL 49653 (b), 10 µM CS 045 (c), 10 µM pioglitazone (d), 100 µM palmitate (e), 100 µM
Northern
blot analyses were performed to investigate the effects of BRL 49563 on
the expression of RNA markers characteristic of either muscle or
adipose differentiation in C2C12N cells (Fig. 3). Cells
maintained in standard medium were clearly differentiated into myotubes
since high levels of muscle-specific form of
Figure 3:
Effects of BRL 49653 on the expression of
myogenic or adipose differentiation markers in C2C12N cells. Cells were
maintained in standard medium until day 5 post-confluence and exposed (lane 2) or not (lane 1) from confluence to 5
µM BRL 49653. 20 µg of total RNA was analyzed by
Northern blot as described under ``Experimental Procedures.''
Similar results have been obtained in three separate
experiments.
We next examined the effects of
the compound on the differentiation process of satellite cells from
thigh muscles of 1-day-old mice. After plating until day 5
post-confluence, satellite cells were maintained in standard medium
supplemented or not with 5 µM BRL 49653. At that time,
cells maintained in standard medium differentiated into myotubes (Fig. 4A), whereas cells exposed to BRL 49653 presented
an adipose-like morphology (Fig. 4B). Northern blot
analyses confirmed these morphological observations, since control
cells expressed high levels of myogenin and
Figure 4:
Effects of BRL 49653 on satellite cell
differentiation. A and B, satellite cells were
isolated from muscle of newborn mice as described under
``Experimental Procedures'' and maintained in standard medium
in the absence (A) or presence (B) of 5 µM BRL 49653 from seeding to 5 days post-confluence. Bars,
0.1 mm. C, RNA (20 µg/lane) from 5 days post-confluent
untreated cells (lane 1) or cells exposed to 5 µM BRL 49653 (lane 2) was analyzed as described in the
legend to Fig. 3. Similar results have been obtained in three
separate experiments.
Figure 5:
Dose-response effects of BRL 49653 and CS
045 on myogenic and adipose marker expression in C2C12N cells. Cells
cultured in standard medium were exposed from day -2 to day
+5 to increasing concentrations of BRL 49653 (filled
symbols) or CS 045 (open symbols). A, RNA was
analyzed as described under ``Experimental Procedures.''
Results are expressed by taking the maximal value obtained for each
probe as 100. Symbols are:
Figure 6:
Time dependence of BRL 49653 effects on
C2C12N cells. Cells cultured in standard medium were exposed for the
indicated period of time to 5 µM BRL 49653. MCK and GPDH
activities were determined at day 5 post-confluence. Results are
presented as described in the legend to Fig. 2and are the mean
± S.D. from three separate
experiments.
To investigate whether or not
the adipose phenotype is inherited, C2C12N cells exposed to 5
µM BRL 49653 from day -2 to day +3 relative to
confluence were replated in standard medium at a 20-fold dilution in
order to promote cell proliferation. These cells were already
differentiated into adipocytes since expressing a high level of GPDH
activity (Fig. 7). After attachment, cells began to proliferate
actively to reach confluence after 5 days. At that time, cells
presented the same morphology as cells which had never been exposed to
the compound and expressed low GPDH activity (35 milliunits/mg of
protein). In addition, these dedifferentiated cells were found to have
recovered the ability to undergo either new myogenic differentiation
when maintained after confluence in standard medium, illustrated by the
induction of MCK and the lack of expression of GPDH, or new adipose
differentiation when exposed to BRL 49653, illustrated by the induction
of GPDH and the lack of expression of MCK (Fig. 7). These
observations demonstrate that induction of the adipose phenotype by BRL
49653 does not require the continuous exposure of nonproliferative
confluent cells. Rather, cell proliferation leads to complete reversion
of this differentiated phenotype.
Figure 7:
Cell proliferation reverses the
adipose-differentiated phenotype of C2C12N cells. Cells exposed from
day -2 to day +3 to 5 µM BRL 49653 were
replated at a 20-fold dilution and maintained in standard medium until
confluence (day 0). After that cells were maintained in the absence (open symbols) or the presence (filled symbols) of 5
µM BRL 49653. MCK (
Figure 8:
Time course of muscle and adipose marker
expression in C2C12N cells exposed or not to BRL 49653. Cells were
maintained in standard medium and exposed (filled symbols) or
not (open symbols) from confluence to 5 µM BRL
49653. RNA was prepared at the indicated time and analyzed as described
in the legend to Fig. 5A. Results are presented as in Fig. 5A and are representative of three independent
experiments. A:
The present study demonstrated that thiazolidinediones and
fatty acids prevent the myogenic differentiation of myoblasts from a
clonal cell line or from primary muscle cell cultures, and also promote
their differentiation into adipose-like cells. Exposure to
thiazolidinediones or to fatty acids drives the developmental fate of
C2C12N myoblasts in an adipogenic direction. At the gene level, these
agents prevent the expression of muscle specific genes such as MCK,
Thiazolidinediones and fatty acids are also able to promote a
similar change in the cell fate of satellite cells from newborn mouse
muscle (36, 37) . When kept in standard medium from
the time of seeding to day 5 post-confluence, about 50% of these cells
differentiate into myotubes and express the muscle markers Several lines of
evidence support the conclusion that thiazolidinediones exert their
effects on non-terminally differentiated C2C12N cells. First, exposure
of fully differentiated myotubes to the drug fails to reverse myotube
formation and to induce adipose differentiation. Second, maximal
adipogenic action of BRL 49653 is observed in cells treated before or
just after confluence, i.e. before expression of the specific
myotube markers. This is also evident morphologically as a complete
differentiation into adipose-like cells is observed in cells exposed
before confluence to the drug, whereas some myotubes still appear in
cultures treated following confluence (Fig. 1, C versus
B). It can also be concluded from our results that chronic
treatment by the inducer is not required for adipose differentiation of
C2C12N cells. Furthermore, the adipoblast commitment is not an
inherited trait since the proliferation of adipose C2C12N cells in
standard medium reverses the differentiated phenotype and leads to the
appearance of cells capable of undergoing either myogenic or adipose
differentiation depending upon the absence or presence of BRL 49653 in
the culture medium. These findings demonstrate that thiazolidinediones
and fatty acids promote the transition from myogenic lineage to that of
adipogenic lineage and that this conversion event occurs at the end of
the growing phase of committed myoblasts. Similar features emerge from
a recent report describing the conversion of the differentiation
pathway of C2C12 myoblasts into osteoblasts upon bone morphogenetic
protein-2 treatment(8) . Taken together, these observations
provide an illustration of the plasticity of the myoblast cell
commitment and of the crucial role exerted by external regulatory
factors, i.e. fatty acids and thiazolidinediones or bone
morphogenetic protein-2, on the fate of these cells toward adipogenic
or osteoblastic cell lineages, respectively. The identification of
the regulatory mechanisms implicated in the action of these external
stimuli could provide interesting information for understanding
mesodermal cell commitment. Clearly, the molecular mechanisms mediating
the adipogenic action of thiazolidinediones and fatty acids in
myoblasts remain to be determined. However, it is tempting to postulate
that FAAR could be involved in this signaling pathway since (i) it has
previously been demonstrated that this nuclear receptor for fatty acids (17) is also activated by thiazolidinediones in preadipose
cells(18) ; and (ii) FAAR mRNA is expressed in C2C12N myoblasts
during the period of time at which thiazolidinediones and fatty acids
exert their adipogenic effects, as shown above. By contrast, the lack
of expression of PPAR In
conclusion, thiazolidinediones and fatty acids are able to withdraw
committed myoblasts from the myogenic differentiation lineage and to
promote the expression of a typical adipose conversion program in these
cells. These findings offer a valuable cellular model to study the
cellular and molecular events of mesodermal cell commitment. In
addition, even if it is premature to conclude that transition from the
myoblast to the adipoblast cell lineage could occur in vivo,
it would be of interest to investigate this possibility in some
pathological states characterized by lipid accumulation in muscle
cells. For instance, such lipid deposition in muscle cells is occurring
in the dystrophic mouse (38) and in mitochondrial
myopathy(39, 40) . In these cases, this phenomenon
could be related to the increase of fatty acid disposal due to both an
increase of fatty acid synthesis and decrease of mitochondrial fatty
acid oxidation. Lipid accumulation has also been described in cardiac
cells from diabetic rats (41) which are characterized by a high
blood fatty acid concentration.
Volume 270,
Number 47,
Issue of November 24, 1995 pp. 28183-28187
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
-actin, and creatine kinase, thus abolishing the formation of
multinucleated myotubes. These treatments lead in parallel to the
expression of a typical adipose differentiation program including
acquisition of adipocyte morphology and activation of adipose-related
genes. A similar transition toward the adipose differentiation pathway
also occurs in mouse muscle satellite cells maintained in primary
culture. Thiazolidinediones exert their adipogenic effects only in
non-terminally differentiated myoblasts; myotubes are insensitive to
the compounds. Continuous exposure to inducers after growth arrest is
not required to maintain the adipose phenotype, but proliferation of
adipose-like C2C12N cells leads to a complete reversion toward
undifferentiated cells able to undergo either myogenic or adipogenic
differentiation depending on the composition of culture medium. These
results indicate that adipogenic inducers, such as thiazolidinediones
or fatty acids, specifically convert the differentiation pathway of
myoblasts into that of adipoblasts.
exerts negative effects on all these differentiation
processes(4) . Other factors, such as bone morphogenetic
protein-2(5) , triggers specific determination of pluripotent
fibroblasts (6) or L6 and C2C12 myoblasts (7, 8) toward the osteoblast lineage. To our
knowledge, factors that are able to promote transition from the
myoblast lineage to that of the adipoblast have not been yet
discovered. Muscle and adipose differentiation involve complex
processes that lead to the induction of several differentiation-linked
genes specifically expressed either in muscle cells, i.e. MyoD, myogenin, -actin, or muscle creatine kinase (MCK), (
)or in adipose cells, i.e. adipocyte lipid binding
protein (ALBP) or hormone-sensitive lipase(9, 10) .
Other genes, such as glycerol-3-phosphate dehydrogenase (GPDH),
lipoprotein lipase, insulin-responsive glucose transporter-4 (Glut-4),
or fatty acid transporter, are expressed in both tissues but at higher
levels in adipose tissue. Factors controlling muscle and adipose
differentiation processes are clearly different. Differentiation of
myoblasts in cell culture is initiated by peptide growth factor
withdrawal (11, 12) while adipose differentiation is
controlled by addition of various hormones and nutrients(10) .
We have shown that long chain fatty acids act in preadipose cells as
adipogenic agents(13, 14, 15, 16) .
These effects of fatty acids are mediated by activation of a nuclear
receptor called fatty acid-activated receptor (FAAR) expressed in a
variety of tissues including adipose tissue and muscle(17) .
FAAR is activated by fatty acids (17) and
thiazolidinediones(18) , a new class of antidiabetic agents,
which have also been described as exerting potent adipogenic effects in
preadipose cell lines(19, 20) . The mode of action of
thiazolidinediones as antidiabetic agents is not yet understood, but it
has been shown that their administration to diabetic animals improves
insulin sensitivity of muscle and adipose
tissue(21, 22) .
Materials
Culture media were obtained from Life
Technologies, Inc. (Cergy-Pontoise, France). Bovine serum and other
chemical products were purchased from Sigma Chimie (Saint-Quentin,
France). Radioactive materials, the random priming kit, Hybond
membranes, and Hyperfilm MP were from Amersham (Les Ullis, France).
Thiazolidinediones were obtained from SmithKline Beecham
Pharmaceuticals (Welwyn, United Kingdom).Cell Culture
C2C12N cells, subcloned from the
C2C12 cell line(23) , were plated at a density of 2 
10
/cm
and grown in Dulbecco's modified
Eagle's medium supplemented with 10% bovine serum, 200 units/ml
penicillin, 50 µg/ml streptomycin (standard medium). Media were
changed every other day and confluence was reached within 5 days.
Thiazolidinediones and fatty acids were dissolved at a concentration of
50 mM in dimethyl sulfoxide. Control experiments were
performed to exclude any effects of dimethyl sulfoxide. Satellite cells
were obtained from thigh muscles of newborn (1 day) Swiss mice
(Janvier, France) as described by Yaffe (24) and plated at a
density of 4 10 cells/cm in standard
medium.Northern Blotting and Enzymatic Assays
RNA samples
were prepared as described by Chomczynski and Sacchi (25) and
analyzed as described previously(26) . Results were quantitated
by densitometry using an LKB Ultroscan KL densitometer. 28 S ribosomal
RNA was monitored as internal standard. MCK and GPDH activities were
assayed as described previously(27, 28) . Protein
content of samples was determined according to Lowry et al.(29) using bovine serum albumin as standard.
Effects of BRL 49653 on C2C12N Cell
Differentiation
C2C12N cells displayed an almost complete
morphology of multinucleated myotubes when maintained in standard
medium from seeding to day 5 post-confluence (Fig. 1A).
Exposure of post-confluent cells to 5 µM BRL 49653 (30) led to a net decrease in the number of multinucleated
myotubes with a parallel appearance of small cells containing lipid
droplets (Fig. 1B). A homogenous monolayer of
lipid-containing cells was observed when the treatment was started 2
days before confluence (Fig. 1C). This phenomenon was
next investigated biochemically by the determination of MCK activity,
as a muscle differentiation marker, and GPDH activity, as an adipocyte
differentiation marker, in C2C12N cells exposed from day -2 to
day +5 relative to confluence to thiazolidinediones, namely BRL
49653, CS 045(20) , and pioglitazone (19) , or various
long chain fatty acids (Fig. 2). C2C12N cells maintained in
standard medium expressed high levels of MCK activity (2250 ±
225 milliunits/mg of protein) and low levels of GPDH activity (24
± 4 milliunits/mg of protein). Exposure to 5 µM BRL
49653, 10 µM CS 045, or 10 µM pioglitazone
led to a strong inhibition of MCK activity and to induction of GPDH
activity. Treatment with 100 µM -linolenic acid or
5,8,11,14-eicosatetraynoic acid also effectively inhibited MCK
expression and induced GPDH expression. Palmitate appeared to be less
effective than polyunsaturated fatty acids in this process.
-linolenate (f), or 100
µM 5,8,11,14-eicosatetraynoic acid (g). Values
obtained with cells maintained in standard medium are taken as 1 and
represent the mean ± S.D. from three separate
experiments.
-actin mRNA and
myogenin mRNA were expressed 5 days after confluence. By contrast,
these cells did not express detectable levels of ALBP, GPDH, and
hormone-sensitive lipase mRNAs, and they showed only weak signals for
Glut-4, lipoprotein lipase, and fatty acid transporter mRNAs. Exposure
to BRL 49653 strongly reduced the expression of myogenin and
-actin mRNAs and led to the emergence of adipose markers including
ALBP, GPDH, and hormone-sensitive lipase mRNAs. Significant increases
in Glut-4, lipoprotein lipase, and fatty acid transporter mRNA
expression were also observed. The level of expression of these mRNAs
at this stage were strikingly similar to those found in fully
differentiated adipose cells from Ob1771 (31) or 3T3-442A (32) cell lines (not shown).
-actin mRNAs and did
not express ALBP and fatty acid transporter mRNAs, whereas BRL
49653-treated cells strongly expressed the adipose markers ALBP and
fatty acid transporter and only weakly expressed the muscle markers (Fig. 4C). Similar results were obtained for satellite
cells exposed to 10 µM CS 045 or 100 µM
linolenic acid instead of BRL 49653 (not shown). Taken together, these
observations strongly suggest that thiazolidinediones and fatty acids
inhibit myogenic differentiation and induce the expression of a typical
adipose differentiation program in C2C12N cells and in primary cultures
of muscle cells.
Potency of Thiazolidinediones on C2C12N Adipose
Differentiation
C2C12N cells maintained in standard medium were
exposed to increasing concentrations of BRL 49653 or CS 045 from day
-2 to day +5 relative to confluence. The potency of the
compounds to change the differentiation pathway of the cells was
evaluated by determining the amounts of myogenin and ALBP mRNAs (Fig. 5A), and of MCK and GPDH enzymatic activities (Fig. 5B). Morphological analysis revealed that,
increasing the concentration of inducer lead, in a dose-dependent
manner, to a decrease in the rate of myotube formation with a
concomitant increase in the appearance of lipid-containing cells in the
whole cell population (not shown). Biochemical parameters reflected
this dual process, since inhibition of muscle markers, i.e. myogenin mRNA and MCK activity, and induction of adipose markers, i.e. ALBP mRNA and GPDH activity, were also dose-dependent.
Both compounds exerted their effects at very low concentrations, BRL
49653 appearing more active than CS 045 with half-maximal effective
concentrations at about 100 and 300 nM, respectively.
,
, myogenin mRNA; 
,
, ALBP mRNA. B, MCK (,
) and GPDH (,
) enzymatic activities were determined in the same cells as in A. Results are presented as in Fig. 2and represent the
mean ± S.D. from three separate
experiments.
Time-dependence of BRL 49653 Effects on Adipose C2C12N
Differentiation
To determine the temporal action of
thiazolidinediones on inhibition of myotube formation and induction of
adipose differentiation, C2C12N cells maintained in standard medium
were exposed for various periods of time to a maximally effective
concentration of BRL 49653. Five days after confluence, the extent of
muscle and adipose differentiation was estimated by determining MCK and
GPDH enzymatic activities (Fig. 6). The maximal adipogenic
effect of the compound, observed in cells treated from day -2 to
day +5 relative to confluence, resulted in a complete absence of
MCK activity and a 24-fold induction of GPDH activity. However, chronic
treatment by BRL 49653 was not required, since cells treated from day
-2 to day 0 or from day 0 to day +3 expressed high GPDH
activities and low MCK activities. By contrast, BRL 49653 appeared to
be ineffective on myotubes as illustrated by the lack of effect on MCK
and GPDH activities in cells maintained until day 3 after confluence in
standard medium and then exposed to the compound for 2 days (Fig. 6) or longer (not shown).
, ) and GPDH (
,
) activities were determined at the indicated time. Results are
presented in milliunits/mg of protein and are the mean ± S.D.
from three separate experiments.
Expression of Nuclear Adipose-regulatory Factors in
C2C12N Cells
To investigate the mechanisms underlying the
adipogenic effect of BRL 49653, expression of nuclear proteins known to
play crucial roles in the control of adipose differentiation, such as
C/EBP(33, 34) , PPAR(35) , and
FAAR(17) , was examined. Fig. 8presents the time course
for induction of mRNAs encoding these proteins in C2C12N cells exposed
or not to 5 µM BRL 49653 at confluence.
-Actin and
ALBP mRNAs were used as indicators of muscle and adipose
differentiation, respectively (Fig. 8A). In cells
maintained in standard medium, -actin mRNA emerged at day 1
post-confluence and accumulated thereafter to reach a maximal
expression at day 5 post-confluence, whereas treatment with BRL 49653
almost completely prevented this accumulation. In contrast, ALBP mRNA
expression was very low in untreated cells, and increased in cells
exposed to the drug to attain maximal levels at day 5. As shown in Fig. 8B, FAAR mRNA was detectable 2 days before
confluence and reached 75% of its maximal expression at confluence.
Exposure of the cells to BRL 49653 led to a moderate, but significant
increase in FAAR mRNA expression. C/EBP and PPAR mRNAs were
below the limit of detection in growing cells and remained undetectable
during the myogenic differentiation of cells kept in standard medium.
Emergence of both mRNAs occurred in parallel to that of ALBP mRNA in
cells exposed to BRL 49653, reaching plateau values at day 5 after
confluence.
, ;
-actin mRNA; ,
, ALBP mRNA. B: , , FAAR mRNA; 
,
, PPAR
mRNA;
, , C/EBP
mRNA.
-actin, and myogenin and lead to the expression of a typical
adipose differentiation program. It is noteworthy that in C2C12N
adipose-like cells the levels of expression of all the adipose-related
genes investigated in this study are quite similar to those found in
fully differentiated cells from adipose cell lines. For the most potent
adipogenic agent, BRL 49653, this dual regulation takes place at low
concentrations with a half-maximal effect of about 100 nM,
indicating that C2C12N myoblasts are more sensitive to BRL 49653 than
preadipose Ob1771 cells in which a stimulatory effect of the compound
on ALBP gene expression is observed over a range of concentration at
least one order of magnitude higher (18) . -actin
and myogenin, whereas chronic exposure to BRL 49653 leads to a nearly
homogeneous monolayer of lipid-containing cells which express high
levels of the adipose markers ALBP and fatty acid transporter, and only
moderate levels of myogenin and -actin mRNAs. and C/EBP
at this cell stage argues
against a regulatory role for these nuclear proteins in the
myoblast/adipoblast cell lineage transition. Rather, it is more likely
that C/EBP and PPAR participate in the regulation of gene
expression during the terminal stages of adipose differentiation given
their late expression in C2C12N cells exposed to BRL 49653.
),
CCAAT/enhancer binding protein-; FAAR, fatty acid-activated
receptor; Glut-4, muscle/adipose insulin-responsive glucose
transporter; GPDH, glycerol-3-phosphate dehydrogenase; PPAR,
peroxisome proliferator-activated receptor-
.
We thank Drs. L. Kozak, C. Holm, M. D. Friedman, and
E. L. Olson for their kind gifts of GPDH, hormone-sensitive lipase,
C/EBP, and myogenin cDNA, respectively. We are grateful to F.
Bonino for expert technical assistance and G. Oillaux for skillful
secretarial assistance. Thanks are due to SmithKline Beecham
Pharmaceuticals for a kind gift of thiazolidinediones. We thank Drs. E.
Van Obberghen-Schilling and G. Ailhaud (UMR 134 CNRS) and Drs. S. A.
Smith and P. Young (SmithKline Beecham Pharmaceuticals) for helpful
discussions and careful reading of the manuscript.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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 S. Eliazer, J. Spencer, D. Ye, E. Olson, and R. L. Ilaria Jr. Alteration of Mesodermal Cell Differentiation by EWS/FLI-1, the Oncogene Implicated in Ewing's Sarcoma Mol. Cell. Biol., January 15, 2003; 23(2): 482 - 492. [Abstract] [Full Text] [PDF]
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 J. Theilhaber, T. Connolly, S. Roman-Roman, S. Bushnell, A. Jackson, K. Call, T. Garcia, and R. Baron Finding Genes in the C2C12 Osteogenic Pathway by k-Nearest-Neighbor Classification of Expression Data Genome Res., January 1, 2002; 12(1): 165 - 176. [Abstract] [Full Text] [PDF]
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 E. C. Person, L. L. Waite, R. N. Taylor, and T. S. Scanlan Albumin Regulates Induction of Peroxisome Proliferator-Activated Receptor-{{gamma}} (PPAR{{gamma}}) by 15-Deoxy-{{Delta}}12-14-Prostaglandin J2 in Vitro and May Be an Important Regulator of PPAR{{gamma}} Function in Vivo Endocrinology, February 1, 2001; 142(2): 551 - 556. [Abstract] [Full Text] [PDF]
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 S. Matthaei, M. Stumvoll, M. Kellerer, and H.-U. Häring Pathophysiology and Pharmacological Treatment of Insulin Resistance Endocr. Rev., December 1, 2000; 21(6): 585 - 618. [Abstract] [Full Text]
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 K. A. J. M. van der Lee, M. M. Vork, J. E. De Vries, P. H. M. Willemsen, J. F. C. Glatz, R. S. Reneman, G. J. Van der Vusse, and M. Van Bilsen Long-chain fatty acid-induced changes in gene expression in neonatal cardiac myocytes J. Lipid Res., January 1, 2000; 41(1): 41 - 47. [Abstract] [Full Text]
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B. Desvergne and W. Wahli Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism Endocr. Rev., October 1, 1999; 20(5): 649 - 688. [Abstract] [Full Text]
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 A. K. El-Jack, J. K. Hamm, P. F. Pilch, and S. R. Farmer Reconstitution of Insulin-sensitive Glucose Transport in Fibroblasts Requires Expression of Both PPARgamma and C/EBPalpha J. Biol. Chem., March 19, 1999; 274(12): 7946 - 7951. [Abstract] [Full Text] [PDF]
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S. Mandrup, R. V. Sorensen, T. Helledie, J. Nohr, T. Baldursson, C. Gram, J. Knudsen, and K. Kristiansen Inhibition of 3T3-L1 Adipocyte Differentiation by Expression of Acyl-CoA-binding Protein Antisense RNA J. Biol. Chem., September 11, 1998; 273(37): 23897 - 23903. [Abstract] [Full Text] [PDF]
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 K. S. Park, T. P. Ciaraldi, K. Lindgren, L. Abrams-Carter, S. Mudaliar, S. E. Nikoulina, S. R. Tufari, J. H. Veerkamp, A. Vidal-Puig, and R. R. Henry Troglitazone Effects on Gene Expression in Human Skeletal Muscle of Type II Diabetes Involve Up-Regulation of Peroxisome Proliferator-Activated Receptor-{gamma} J. Clin. Endocrinol. Metab., August 1, 1998; 83(8): 2830 - 2835. [Abstract] [Full Text]
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F. M. GREGOIRE, C. M. SMAS, and H. S. SUL Understanding Adipocyte Differentiation Physiol Rev, July 1, 1998; 78(3): 783 - 809. [Abstract] [Full Text] [PDF]
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 S. E. McGowan, S. K. Jackson, M. M. Doro, and P. J. Olson Peroxisome proliferators alter lipid acquisition and elastin gene expression in neonatal rat lung fibroblasts Am J Physiol Lung Cell Mol Physiol, December 1, 1997; 273(6): L1249 - L1257. [Abstract] [Full Text] [PDF]
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G. Martin, K. Schoonjans, A.-M. Lefebvre, B. Staels, and J. Auwerx Coordinate Regulation of the Expression of the Fatty Acid Transport Protein and Acyl-CoA Synthetase Genes by PPARalpha and PPARgamma Activators J. Biol. Chem., November 7, 1997; 272(45): 28210 - 28217. [Abstract] [Full Text] [PDF]
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 A.-M. Lefebvre, J. Peinado-Onsurbe, I. Leitersdorf, M. R. Briggs, J. R. Paterniti, J.-C. Fruchart, C. Fievet, J. Auwerx, and B. Staels Regulation of Lipoprotein Metabolism by Thiazolidinediones Occurs through a Distinct but Complementary Mechanism Relative to Fibrates Arterioscler. Thromb. Vasc. Biol., September 1, 1997; 17(9): 1756 - 1764. [Abstract] [Full Text]
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S. Mandrup and M. D. Lane Regulating Adipogenesis J. Biol. Chem., February 28, 1997; 272(9): 5367 - 5370. [Full Text] [PDF]
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R P Brun, P Tontonoz, B M Forman, R Ellis, J Chen, R M Evans, and B M Spiegelman Differential activation of adipogenesis by multiple PPAR isoforms. Genes & Dev., April 15, 1996; 10(8): 974 - 984. [Abstract] [PDF]
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J. G. Hunter, M. F. van Delft, R. A. Rachubinski, and J. P. Capone Peroxisome Proliferator-activated Receptor gamma Ligands Differentially Modulate Muscle Cell Differentiation and MyoD Gene Expression via Peroxisome Proliferator-activated Receptor gamma -dependent and -independent Pathways J. Biol. Chem., October 5, 2001; 276(41): 38297 - 38306. [Abstract] [Full Text] [PDF]
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