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From
Received for publication, September 7, 1999, and in revised form, March 13, 2000
Fibrates and glitazones are two classes of drugs
currently used in the treatment of dyslipidemia and insulin resistance
(IR), respectively. Whereas glitazones are insulin sensitizers acting via activation of the peroxisome proliferator-activated receptor (PPAR)
MS,1 which develops as a
result of IR (1), is characterized by glucose intolerance,
hyperinsulinemia, dyslipidemia, and hypertension. These metabolic
abnormalities are frequently associated with visceral obesity (2). The
clustering of multiple cardiovascular risk factors in MS results in
increased risk for atherosclerotic vascular disease, the major cause of
mortality and morbidity in type 2 diabetic patients (3).
Pharmacological treatment of MS should therefore aim at ameliorating IR
and reducing cardiovascular risk factors.
The PPAR nuclear receptors are important regulators of glucose and
lipid homeostasis, which are activated by two classes of drugs:
fibrates and glitazones (4). Glitazones are PPAR Results from the Helsinki Heart Study demonstrated that fibrates
significantly reduce the incidence of cardiovascular disease in
patients with type 2 diabetes (19). Fibrates are hypolipidemic drugs
that are very efficient in lowering elevated triglyceride concentrations consistently observed in these patients (20). The action
of fibrates on lipid metabolism is mediated principally by activation
of PPAR Animals--
A first series of experiments was performed on male
C57BL/6 mice, 8 weeks of age at the start of the experiment, which were randomly assigned to three different diets for 14 weeks. The mice received a low fat diet (UAR AO4), a high fat diet containing coconut
oil (29% w/w) as described (24), or the same high fat diet
supplemented with fenofibrate (0.05% w/w). A second series of
experiments was performed with male Zucker rats of different ages,
either bred at the U465 INSERM animal facility from pairs originally
provided by the Harriet G. Bird Laboratory (Stow, MA) or obtained from
Iffa-Credo (L'Arbresle, France). In the first experiment, 5-week-old
obese fa/fa Zucker rats (n = 6 per group; U465 INSERM
breeding facility) were fed a standard diet with or without
ciprofibrate (0.005% w/w) for 15 days and subsequently subjected to an
intravenous glucose tolerance test (IVGTT). In the second experiment, 8 lean Fa/? and 14 obese fa/fa 21-week-old Zucker rats (Iffa-Credo
breeding facility) were randomized in two groups per genotype, based on
base-line body weight and serum triglyceride and glucose
concentrations. Rats of each group were given a standard rat diet with
or without ciprofibrate (0.005% w/w) for 21 days. In the third
experiment, 12 obese fa/fa 20-week-old Zucker rats (U465 INSERM
breeding facility) were randomized in two groups/genotype based on
base-line body weight and treated for 9 days once daily by oral gavage
with GW9578 (5 mg/kg/day) (25) or vehicle.
The food intake of the animals was carefully monitored by weighing
special gridded metal food containers at regular intervals. In all
experiments, body weights were monitored throughout the treatment
period. Except when glucose tolerance tests were performed, food was
removed at 8 a.m. and blood samples collected 4 h later at
the end of the treatment. Animals were euthanized and tissues collected
and weighed. Serum or plasma was isolated and stored at Intravenous Glucose Tolerance Test--
Animals were
anesthetized at 2:00 p.m. after a 5-h fast by an intraperitoneal
injection of sodium pentobarbital (50 mg/kg). Rats were injected with
glucose (0.55 g/kg) in the saphenous vein and blood samples were
collected from the tail vein in heparinized tubes at 0, 5, 10, 15, 20, and 30 min after the glucose load. Samples were kept on ice, and plasma
was isolated and stored at Serum Assays--
Glucose concentrations were measured
using enzymatic methods, insulin (CIS Bio) and leptin (Linco) by radioimmunoassay.
RNA Analysis--
RNA extractions and Northern blot analysis of
total cellular RNA (7) were performed using human LPL (7), mouse
lep (14), rat CD36/FAT (26), and internal control 36B4
probes and quantified by PhosphorImager analysis.
To determine whether selective PPAR The influence of fenofibrate on glucose homeostasis was first analyzed
in C57BL/6 mice, which develop obesity and IR when fed a high fat diet
(24). Feeding C57BL/6 mice with the high fat diet resulted in
hyperinsulinemia and mild hyperglycemia, which were both corrected by
low dose fenofibrate treatment (Fig. 1,
A and B). By contrast, treatment of chow-fed
C57BL/6 mice (n = 10/group) during 10 weeks with
fenofibrate (0.1% w/w) incorporated in the diet did not influence
serum glucose (untreated: 1.89 ± 0.33 versus treated:
2.03 ± 0.48 g/liter) or insulin (untreated: 17.6 ± 6.0 versus treated: 16.3 ± 7.8 microunits/ml)
concentrations, indicating that the effects of fenofibrate on glucose
homeostasis occur only in IR fat-fed mice.
Interestingly, fenofibrate treatment prevented the high fat
diet-induced increase in body weight (Fig.
2) and adipose tissue mass (Fig. 1,
C and D). Identical results were obtained in a
separate experiment with C57BL/6 mice submitted to the same nutritional protocol (Fig. 3). In these animals,
serum leptin concentrations were measured and found to be positively
correlated with body weight and epididymal adipose tissue weight, a
relationship that was not influenced by fenofibrate treatment (Fig. 3).
These observations indicate that fenofibrate does not exert a specific
regulatory effect on leptin production. Interestingly, despite lower
leptin concentrations, food intake was not increased in the mice fed the fenofibrate-enriched diet (13.8 ± 1.0 kcal/day/animal;
n = 14) versus high fat diet alone
(13.8 ± 0.9 kcal/day/animal; n = 14). These data
further show that the effects of fenofibrate on glucose homeostasis,
body weight, and adipose tissue mass are not driven by a
reduction in caloric intake.
Peroxisome Proliferator-activated Receptor
Activators Improve
Insulin Sensitivity and Reduce Adiposity*
,
,
Unité 465, INSERM, Institut
Biomédical des Cordeliers, F-75006 Paris, France,
§ Unité 325, INSERM, Département
d'Athérosclérose, Institut Pasteur de Lille, F-59019
Lille, France, the Faculté de Pharmacie, Université de
Lille II, F-59006 Lille, France, the ¶ Department of Clinical
Biology, Division of Biochemistry, University of Bergen, Haukeland
Hospital, N-5021 Bergen, Norway, Sanofi Recherche, F-31036
Toulouse, France, and ** Glaxo Wellcome Research and Development,
Research Triangle Park, North Carolina 27709
ABSTRACT
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
subtype, fibrates exert their lipid-lowering activity via PPAR
.
To determine whether PPAR activators also improve insulin
sensitivity, we measured the capacity of three PPAR-selective agonists, fenofibrate, ciprofibrate, and the new compound GW9578, in
two rodent models of high fat diet-induced (C57BL/6 mice) or genetic
(obese Zucker rats) IR. At doses yielding serum concentrations shown to
activate selectively PPAR, these compounds markedly lowered
hyperinsulinemia and, when present, hyperglycemia in both animal
models. This effect relied on the improvement of insulin action on
glucose utilization, as indicated by a lower insulin peak in response
to intraperitoneal glucose in ciprofibrate-treated IR obese Zucker
rats. In addition, fenofibrate treatment prevented high fat
diet-induced increase of body weight and adipose tissue mass without
influencing caloric intake. The specificity for PPAR activation
in vivo was demonstrated by marked alterations in the expression of PPAR target genes, whereas PPAR target gene
mRNA levels did not change in treated animals. These results
indicate that compounds with a selective PPAR activation profile
reduce insulin resistance without having adverse effects on body weight and adipose tissue mass in animal models of IR.
INTRODUCTION
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
activators, currently used for the treatment of IR and type 2 diabetes (5). These
compounds increase fatty acid (FA) uptake in adipose tissue (6), due to
PPAR-mediated induction of lipoprotein lipase (LPL) and FA
transporter proteins (7, 8). These actions are considered major
determinants of the effects of glitazones on glucose homeostasis, since
they favor the diversion of FA from muscles resulting in a relief of
inhibition of peripheral glucose utilization (6). In addition,
glitazones may also act by ameliorating TNF-induced insulin
resistance (9-11). However, PPAR activation also enhances adipose
differentiation and fat storage (12). Moreover, glitazones increase
food intake (13, 14), at least in part through the repression of leptin
gene expression in adipose tissue (14, 15). This action is likely to be
mediated via PPAR since heterozygous PPAR-deficient mice display
increased adipose tissue leptin expression accompanied with lowered
food intake (16). Accordingly, increased body weight gain (13, 17) and
adipose tissue mass (14) have been reported in rodents upon glitazone
treatment, a feature that might also occur in humans (18).
leading to altered expression of genes involved in lipid and
lipoprotein metabolism in liver (21). Since fibrate treatment results
in increased hepatic oxidation of fatty acids and reduced synthesis and
secretion of triglycerides (20), as well as decreased plasma
concentrations of cytokines, such as TNF (22, 23), we hypothesized
that selective PPAR activators might also improve glucose
homeostasis. To test this hypothesis, we assessed therefore the
influence of selective PPAR activators on glucose homeostasis
and body weight control in animal models of IR.
EXPERIMENTAL PROCEDURES
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
20 °C
until further analysis.
20 °C until analysis.
RESULTS
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
activators influence
insulin and glucose homeostasis, experiments were performed in animal models of IR using ciprofibrate and fenofibrate, which are the most
PPAR-selective fibrates currently available in clinics, as well as
with the novel PPAR subtype-selective agonist GW9578 (25). Results
from in vitro transactivation assays demonstrated that
ciprofibrate (data not shown) and fenofibrate (25) activate PPAR
with EC50 values of 20 and 30 µM,
respectively, whereas PPAR is only marginally activated by any of
these compounds (EC50 value for PPAR of 300 and >300
µM for fenofibrate and ciprofibrate respectively).
Neither ciprofibrate nor fenofibrate activates PPAR
(Ref. 25 and
data not shown). The third compound, GW9578, was chosen on the basis of
its high activity and specificity for PPAR, with EC50
values for murine PPAR of 5 nM (as opposed to 1.5 µM for PPAR and 2.6 µM for PPAR)
(25).
View larger version (23K):
[in a new window]
Fig. 1.
Fenofibrate inhibits high fat diet-induced
hyperinsulinemia, hyperglycemia, and increase of adipose tissue mass in
C57BL/6 mice. 8-Week-old male C57BL/6 mice (n = 14/group) were treated for 14 weeks with a low fat diet, a high fat
diet, or a high fat diet supplemented with fenofibrate (FF;
0.05% w/w), and serum insulin (A) and glucose
(B) concentrations and epididymal (C) and
perirenal (D) adipose tissue mass was measured. Results are
expressed as the mean ± S.D. Statistically significantly
differences (ANOVA, p < 0.005) between groups are
indicated by different letters.
View larger version (28K):
[in a new window]
Fig. 2.
Fenofibrate inhibits high fat diet-induced
body weight gain in C57BL/6 mice. Male C57BL/6 mice
(n = 14/group) were treated as indicated under
Fig. 1. Body weights are expressed as the mean ± S.E. Body
weights at the end of the treatment period are statistically
significantly different (ANOVA, p < 0.01) between the
high fat group and the chow and high fat plus fenofibrate groups,
respectively.
View larger version (18K):
[in a new window]
Fig. 3.
The positive correlation between leptin and
body weight (A) or epididymal adipose tissue weight
(B) is not influenced by fenofibrate treatment in
C57BL/6 mice. Male C57BL/6 mice (n = 6/group) were
treated as indicated under Fig. 1. Body and epididymal adipose tissue
weights and serum leptin concentrations were measured at the end of the
treatment period.
To evaluate which PPAR subtype was activated in vivo,
Northern blot analysis of PPAR- and PPAR-specific target gene
expression was performed. To this aim, the mRNA levels of the gene
coding for the fatty acid transporter CD36/FAT, which has been
implicated in the development of the IR syndrome (27), were measured
based on the observation that its expression is regulated in a
tissue-selective manner by activators of PPAR in liver and PPAR
in adipose tissue (28). In the C57BL/6 mice treated with fenofibrate, a
marked increase in CD36/FAT mRNA levels were observed in the liver,
whereas mRNA levels of CD36/FAT remained unchanged in epididymal
adipose tissue (Fig. 4). These
observations suggest that fenofibrate treatment resulted in selective
activation of PPAR in liver, but not of PPAR in adipose tissue of
these mice.
|
To test whether PPAR activators might also improve glucose
homeostasis in another model of IR, we chose the obese Zucker rat,
which bears a mutation in the leptin receptor gene resulting in early
onset obesity and marked hyperinsulinemia (29). Depending on the
genetic background, these rats may also develop hyperglycemia later in
life. Ciprofibrate treatment of 5-week-old obese Zucker rats lowered
body weight gain and epididymal adipose tissue mass and reduced plasma
insulin concentrations by almost 50% (Table I). Furthermore, the plasma insulin
response to glucose during IVGTT was markedly decreased (Fig.
5), demonstrating a clear-cut improvement
of insulin action on glucose utilization. Serum glucose concentrations
and IVGTT glucose curves were normal and comparable between treated and
untreated obese rats (Table I and Fig. 5).
|
|
In older obese Zucker rats, ciprofibrate treatment significantly
decreased serum insulin concentrations (Fig.
6), even though the insulin levels in
these animals remained still higher than in age-matched lean (Fa/?)
rats (insulinemia: 45 ± 8 microunits/ml; n = 4).
In these obese rats, which have developed increased blood glucose
concentrations at the age of 24 weeks, ciprofibrate treatment also
decreased serum glucose concentrations (Fig. 6). In contrast to the
observation in young obese Zucker rats, no change was detectable in
body weight (Fig. 6) and adipose tissue mass (data not shown) at this
age. Nevertheless, serum leptin concentrations were slightly decreased
(Fig. 6), suggesting that adipose tissue tended to be reduced.
Ciprofibrate treatment was without effect on serum insulin (untreated,
n = 4: 45 ± 8; treated, n = 4:
53 ± 5 microunits/ml), glucose (untreated, n = 4:
1.2 ± 0.1; treated, n = 4: 1.0 ± 0.1 g/liter) and leptin (untreated, n = 4: 7.4 ± 0.8;
treated, n = 4: 6.7 ± 1.0 ng/ml) concentrations
in lean Zucker rats of the same age.
|
At the dose administered to the obese Zucker rats, peak serum
concentrations of ciprofibrate of 91 ± 3 µM were
reached indicating, based on the EC50 values for PPAR
(20 µM) and PPAR (> 300 µM) activation,
that ciprofibrate likely activates selectively PPAR in the obese
rats. This was further demonstrated by a marked increase in CD36/FAT
mRNA levels observed in the liver, with no change in both
epididymal and perirenal adipose tissue (Fig.
7A). Furthermore, mRNA
levels of LPL and leptin, two other genes regulated by PPAR, but not
by PPAR activators in adipose tissue of rats (7, 14, 15), were
similar in epididymal adipose tissue of treated and control animals
(LPL: untreated, n = 7:100 ± 16%
versus treated, n = 7:109 ± 11%;
lep: untreated, n = 7:100 ± 18%
versus treated, n = 7:126 ± 8%). By
contrast, hepatic mRNA levels of the PPAR target genes (21, 28)
apoA-I (untreated, n = 7:100 ± 37%
versus treated, n = 7:35 ± 12%) and
apoC-III (untreated, n = 7:100 ± 12%
versus treated, n = 7:35 ± 4%) were
significantly affected by ciprofibrate treatment. In addition, the
activity and mRNA levels of CPT-I and CPT-II as well as
-oxidation rates in the liver were significantly enhanced by
ciprofibrate treatment (data not shown). These data indicate that
ciprofibrate treatment results in selective PPAR, but not PPAR
activation in these obese Zucker rats.
|
Similar results were obtained in a separate series of old obese Zucker
rats treated for 9 days with the highly specific PPAR agonist GW9578
(25). In contrast to the ciprofibrate experiment, these obese Zucker
rats were still normoglycemic at the age of 21 weeks, but serum insulin
concentrations were significantly elevated, indicating a state of
insulin resistance. Treatment with GW9578 resulted in markedly reduced
serum insulin concentrations, whereas serum glucose levels were not
affected (Fig. 6). Neither serum leptin levels nor body weights were
changed, probably due to the short time of treatment in this particular
experiment (Fig. 6). No effect of the treatment was observed on food
consumption (untreated: 25.6 ± 6.7 g/day versus
treated:25.0 ± 3.2 g/day), precluding an effect via dietary
changes. When mRNA levels of CD36/FAT were measured, a pronounced
increase of liver CD36/FAT mRNA levels was observed, whereas both
epididymal and perirenal adipose tissue CD36/FAT mRNA levels
remained unchanged after GW9578 treatment (Fig. 7). Furthermore, GW9578
treatment did not influence LPL or leptin mRNA levels in both
adipose tissue depots (data not shown). Thus, as with ciprofibrate,
treatment with GW9578 resulted in efficient PPAR activation, whereas
PPAR was not activated in these animals.
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EXPERIMENTAL PROCEDURES
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DISCUSSION
REFERENCES
|
|---|
Previous studies have demonstrated that certain naturally
occurring and -substituted FA (such as conjugated linoleic acid and
MEDICA 16) (30, 31) and the fibrate bezafibrate (32) improve insulin
sensitivity and normalize impaired glucose tolerance in rat models of
IR. In humans bezafibrate may also improve glucose homeostasis
(33-35). Although fatty acids are PPAR activators, they also
activate PPAR and PPAR equally well (36). Similarly, in contrast
to ciprofibrate and fenofibrate, bezafibrate activates PPAR,
PPAR, and PPAR with comparable EC50 values (PPAR:
50; PPAR: 60 µM; PPAR: 20 µM; Ref.
25). Therefore, it is impossible to conclude via which PPAR form the
effects of these compounds on glucose homeostasis are mediated. In the
present study we demonstrate that, in two models of diet-induced and
genetic obesity-linked IR, PPAR activators correct elevated serum
glucose and insulin concentrations by increasing insulin action on
glucose utilization. Most importantly, fibrate PPAR activators also
decrease adipose tissue mass, by a mechanism independent of changes in
food intake and leptin gene expression. This effect is in sharp
contrast to PPAR activators, which increase body weight (13, 17, 18) and epididymal adipose tissue mass in rodents (14).
Several lines of evidence indicate that the nuclear receptor PPAR
mediates the actions of ciprofibrate, fenofibrate and GW9578 on glucose
homeostasis. First, based on the EC50 values of these compounds for the different PPARs and their serum concentrations attained in the obese Zucker rats, ciprofibrate and fenofibrate likely
activate PPAR maximally, whereas PPAR activation is negligible. Furthermore, ciprofibrate treatment increased mitochondrial
-oxidation and serum concentrations of ketone bodies (data not
shown) in obese Zucker rats, which is consistent with PPAR
activation. This is in contrast to the effect of glitazone PPAR
activators, which decrease serum ketone bodies (37, 38) and have either no effect on (39) or may even decrease fatty acid oxidation (6, 38).
Second, treatment of obese Zucker rats with the highly specific PPAR
ligand GW9578 resulted in a decrease of serum insulin concentrations.
Finally, whereas glitazones have been shown to markedly influence gene
expression in adipose tissue of both normal and obese Zucker rats (7,
13, 28), GW9578 and ciprofibrate did not influence the expression of
any known PPAR target genes, including CD36/FAT, in adipose tissue.
In sharp contrast, PPAR target gene expression in liver was
significantly altered. These data provide in vivo evidence
for selective activation of PPAR, but not PPAR in the
ciprofibrate- and GW9578-treated Zucker rats as well as in the
fenofibrate-treated C57BL/6 mice.
Although not the subject of the present study, PPAR ligands may
influence body weight and glucose homeostasis through different mechanisms. At the doses employed in the present study, fibrates do not
appear to have major effects on adipose tissue (present study and Refs.
7 and 8). In contrast, fibrates increase hepatic -oxidation in obese
Zucker rats (data not shown). This catabolic action on FA would result
in an increased FA flux from peripheral tissues, such as skeletal
muscle and adipose tissue, to the liver, a decreased FA synthesis, and
a lowered delivery of triglycerides to peripheral tissues. As such
fibrates might alleviate the FA-mediated inhibition of
insulin-stimulated oxidative and non-oxidative glucose disposal in
skeletal muscle (40, 41), thus ameliorating IR. Furthermore, by
lowering plasma triglycerides, fibrates may decrease skeletal muscle
triglyceride content, which is significantly related to IR and obesity
(42). As an alternative or concomitant mechanism, fibrates might
improve insulin action by decreasing production of cytokines, such as
interleukin-6 and TNF. TNF concentrations are increased in IR
obese humans (43) and Zucker rats (44), as well as in rodents fed a
high fat diet (45). This cytokine has been implicated in the
development of IR by interfering negatively with insulin signaling
(44). In support for this hypothesis is the demonstration that PPAR
activators inhibit NF
B signaling, resulting in lowered production of
cytokines by smooth muscle cells and decreased plasma concentrations of cytokines (22, 23). Interestingly, such a mechanism has also been
suggested to participate, at least in part, in the insulin-sensitizing effect of glitazone PPAR activators (11, 46). Finally, it cannot be
excluded that PPAR agonists exert direct insulin-sensitizing actions.
In contrast to glitazones, which are high affinity PPAR ligands, the
current clinically used fibrates are low affinity PPAR ligands. In
conclusion, the results from this study suggest that PPAR ligands
with higher affinity, in addition to being useful for the treatment of
dyslipidemia, may also be of use to improve insulin sensitivity.
Further studies in patients with MS are required to determine whether
highly active and selective PPAR agonists also improve glucose
homeostasis in man.
| |
ACKNOWLEDGEMENTS |
|---|
We thank C. Ilic and V. Guilbert for technical contributions and K. Kristiansen for providing us the CD36/FAT cDNA.
| |
FOOTNOTES |
|---|
* This work was supported by grants from the Région Nord-Pas de Calais, Sanofi Winthrop, INSERM, and Institut Pasteur de Lille.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: U.325 INSERM,
Dépt. d'Athérosclérose, Inst. Pasteur de Lille, 1 Rue Calmette, 59019 Lille, France. Tel.: 33-3-20-87-73-88; Fax:
33-3-20-87-73-60; E-mail: bart.staels@pasteur-lille.fr.
Published, JBC Papers in Press, March 21, 2000, DOI 10.1074/jbc.M907421199
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ABBREVIATIONS |
|---|
The abbreviations used are:
MS, metabolic
syndrome;
IR, insulin resistance;
PPAR, peroxisome
proliferator-activated receptor;
ANOVA, analysis of variance;
LPL, lipoprotein lipase;
IVGTT, intravenous glucose tolerance test;
FA, fatty acid;
TNF, tumor necrosis factor .
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REFERENCES |
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|
|---|
| 1. | Reaven, G. M. (1993) Annu. Rev. Med. 44, 121-131 |
| 2. | Despres, J. P. (1993) Nutrition 9, 452-459 |
| 3. | Despres, J. P., and Marette, A. (1994) Curr. Opin. Lipidol. 5, 274-289 |
| 4. | Schoonjans, K., Martin, G., Staels, B., and Auwerx, J. (1997) Curr. Opin. Lipidol. 8, 159-166 |
| 5. | Saltiel, A. R., and Olefsky, J. M. (1996) Diabetes 45, 1661-1669 |
| 6. | Oakes, N. D., Camilleri, S., Furler, S. M., Chisholm, D. J., and Kraegen, E. W. (1997) Metabolism 46, 935-942 |
| 7. | Schoonjans, K., Peinado-Onsurbe, J., Lefebvre, A.-M., Heyman, R. A., Briggs, M., Deeb, S., Staels, B., and Auwerx, J. (1996) EMBO J. 15, 5336-5348 |
| 8. | Martin, G., Schoonjans, K., Lefebvre, A.-M., Staels, B., and Auwerx, J. (1997) J. Biol. Chem. 272, 28210-28217 |
| 9. | Peraldi, P., Xu, M., and Spiegelman, B. (1997) J. Clin. Invest. 100, 1863-1869 |
| 10. | Souza, S. C., Yamamoto, M. T., Franciosa, M. D., Lien, P., and Greenberg, A. S. (1998) Diabetes 47, 691-695 |
| 11. | Miles, P. D. G., Romeo, O. M., Higo, K., Cohen, A., Rafaat, K., and Olefsky, J. (1997) Diabetes 46, 1678-1683 |
| 12. | Tontonoz, P., Hu, E., and Spiegelman, B. M. (1994) Cell 79, 1147-1156 |
| 13. | Hallakou, S., Doaré, L., Foufelle, F., Kergoat, M., Guerre-Millo, M., Berthault, M.-F., Dugail, I., Morin, J., Auwerx, J., and Ferré, P. (1997) Diabetes 46, 1393-1399 |
| 14. | De Vos, P., Lefebvre, A. M., Miller, S. G., Guerre-Millo, M., Wong, K., Saladin, R., Hamann, L., Staels, B., Briggs, M. R., and Auwerx, J. (1996) J. Clin. Invest. 98, 1004-1009 |
| 15. | Zhang, B., Graziano, M. P., Doebber, T. W., Leibowitz, M. D., White-Carrington, S., Szalkowski, D. M., Hey, P. T., Wu, M., Cullinan, C. A., Bailey, P., Lollmann, B., Frederich, R., Flier, J. S., Strader, C. D., and Smith, R. G. (1996) J. Biol. Chem. 271, 9455-9459 |
| 16. | Kubota, N., Terauchi, Y., Miki, H., Tamemoto, H., Yamauchi, T., Komeda, K., Satoh, S., Nakano, R., Ishii, C., Sugiyama, T., Eto, K., Tsubamoto, Y., Okuno, A., Murakami, K., Sekihara, H., Hasegawa, G., Naito, M., Toyoshima, Y., Tanaka, S., Shiota, K., Kitamura, T., Fujita, T., Ezaki, O., Aizawa, S., Nagai, R., Tobe, K., Kimura, S., and Kadowaki, T. (1999) Mol. Cell 4, 597-609 |
| 17. | de Souza, C. J., Yu, J. H., Robinson, D. D., Ulrich, R. G., and Meglasson, M. D. (1995) Diabetes 44, 984-991 |
| 18. | Schwartz, S., Raskin, P., Fonseca, V., and Graveline, J. F. (1998) N. Engl. J. Med. 338, 861-866 |
| 19. | Huttunen, J., Manninen, V., Manttari, M., Koskinen, P., Romo, M., Tenkanen, L., Heinonen, O., and Frick, M. (1991) Ann. Med. 23, 155-159 |
| 20. | Staels, B., Dallongeville, J., Auwerx, J., Schoonjans, K., Leitersdorf, E., and Fruchart, J.-C. (1998) Circulation 98, 2088-2093 |
| 21. | Peters, J. M., Hennuyer, N., Staels, B., Fruchart, J.-C., Fievet, C., Gonzalez, F. J., and Auwerx, J. (1997) J. Biol. Chem. 272, 27307-27312 |
| 22. | Staels, B., Koenig, W., Habib, A., Merval, R., Lebret, M., Pineda Torra, I., Delerive, P., Fadel, A., Chinetti, G., Fruchart, J.-C., Najib, J., Maclouf, J., and Tedgui, A. (1998) Nature 393, 790-793 |
| 23. | Madej, A., Okopien, B., Kowalski, J., Zielinski, M., Wysocki, J., Szygula, B., Kalina, Z., and Herman, Z. S. (1998) Int. J. Clin. Pharmacol. Ther. 36, 345-349 |
| 24. | Surwit, R. S., Feinglos, M. N., Rodin, J., Sutherland, A., Petro, A. E., Opara, E. C., Kuhn, C. M., and Rebuffé-Scrive, M. (1995) Metabolism 44, 645-651 |
| 25. | Brown, P. J., Winegar, D. A., Plunket, K. D., Moore, L. B., Lewis, M. C., Wilson, J. G., Sundseth, S. S., Koble, C. S., Wu, Z., Chapman, J. M., Lehmann, J. M., Kliewer, S. A., and Willson, T. M. (1999) J. Med. Chem. 42, 3785-3788 |
| 26. | Abumrad, N. A., El-Maghrabi, M. R., Amri, E.-Z., Lopez, E., and Grimaldi, P. A. (1993) J. Biol. Chem. 268, 17665-17668 |
| 27. | Aitman, T. J., Glazier, A. M., Wallace, C. A., Cooper, L. D., Norsworthy, P. J., Wahid, F. N., Al-Majali, K. M., Trembling, P. M., Mann, C. J., Shoulders, C. C., Graf, D., St. Lezin, E., Kurtz, T. W., Kren, V., Pravenec, M., Ibrahimi, A., Abumrad, N. A., Stanton, L. W., and Scott, J. (1999) Nat. Genet. 21, 76-83 |
| 28. | Motojima, K., Passilly, P., Peters, J. M., Gonzalez, F. J., and Latruffe, N. (1998) J. Biol. Chem. 273, 16710-16714 |
| 29. | Bazin, R., and Lavau, M. (1982) J. Lipid. Res. 23, 839-849 |
| 30. | Houseknecht, K. L., Vanden Heuvel, J. P., Moya-Camarena, S. Y., Portocarrero, C. P., Peck, L. W., Nickel, K. P., and Belury, M. A. (1998) Biochem. Biophys. Res. Commun. 244, 678-682 |
| 31. | Mayorek, N., Kalderon, B., Itach, E., and Bar-Tana, J. (1997) Diabetes 46, 1958-1964 |
| 32. | Matsui, H., Okumura, K., Kawakami, K., Hibino, M., Tki, Y., and Ito, T. (1997) Diabetes 46, 348-353 |
| 33. | Jones, I. R., Swai, A., Taylor, R., Miller, M., Laker, M. F., and Alberti, G. (1990) Diabetes Care 13, 855-863 |
| 34. | Mikhailides, D. P., Mathur, S., Barradas, M. A., and Dandoma, P. (1990) J. Cardiovasc. Pharmacol. 16 Suppl. 9, 26-29 |
| 35. | Inoue, I., Takahashi, K., Katayama, S., Akabane, S., Negishi, K., Suzuki, M., Ishii, J., and Kawazu, S. (1994) Diabetes Res. Clin. Pract. 25, 199-205 |
| 36. | Willson, M. T., and Wahli, W. (1997) Curr. Opin. Chem. Biol. 1, 235-241 |
| 37. | Oakes, N. D., Kennedy, C. J., Jenkins, A. B., Laybutt, D. R., Chisholm, D. J., and Kraegen, E. W. (1994) Diabetes 43, 1203-1210 |
| 38. | Inoue, I., Takahashi, K., Katayama, S., Harada, Y., Negishi, K., Itabashi, A., and Ishii, J. (1995) Metabolism 44, 1626-1630 |
| 39. | Murakami, K., Tobe, K., Ide, T., Mochizuki, T., Ohashi, M., Akanuma, Y., Yazaki, Y., and Kadowaki, T. (1998) Diabetes 47, 1841-1847 |
| 40. | Randle, P. J., Garland, P. B., Hales, C. N., and Newsholme, E. A. (1963) Lancet I, 785-794 |
| 41. | Boden, G., Chen, X., Ruiz, J., White, J. V., and Rossetti, L. (1994) J. Clin. Invest. 93, 2438-2446 |
| 42. | Goodpaster, B. H., and Kelley, D. E. (1998) Curr. Opin. Lipidol. 9, 231-236 |
| 43. | Hotamisligil, G. S., Arner, P., Caro, J. F., Atkinson, R. L., and Spiegelman, B. M. (1995) J. Clin. Invest. 95, 2409-2415 |
| 44. | Hotamisligil, G. S., Shargill, N. S., and Spiegelman, B. M. (1993) Science 259, 87-91 |
| 45. | Morin, C. L., Eckel, R. H., Marcel, T., and Pagliassotti, M. J. (1997) Endocrinology 138, 4665-4671 |
| 46. | Jiang, C., Ting, A. T., and Seed, B. (1998) Nature 391, 82-86 |
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|
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|
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|
|
|
|
 |
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|
|
|
 |
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|
|
|
|
 |
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
 N. D. Oakes, P. Thalen, T. Hultstrand, S. Jacinto, G. Camejo, B. Wallin, and B. Ljung Tesaglitazar, a dual PPAR{alpha}/{gamma} agonist, ameliorates glucose and lipid intolerance in obese Zucker rats Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2005; 289(4): R938 - R946. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Koh, S. H. Han, M. J. Quon, J. Yeal Ahn, and E. K. Shin Beneficial Effects of Fenofibrate to Improve Endothelial Dysfunction and Raise Adiponectin Levels in Patients With Primary Hypertriglyceridemia Diabetes Care, June 1, 2005; 28(6): 1419 - 1424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Reifel-Miller, K. Otto, E. Hawkins, R. Barr, W. R. Bensch, C. Bull, S. Dana, K. Klausing, J.-A. Martin, R. Rafaeloff-Phail, et al. A Peroxisome Proliferator-Activated Receptor {alpha}/{gamma} Dual Agonist with a Unique in Vitro Profile and Potent Glucose and Lipid Effects in Rodent Models of Type 2 Diabetes and Dyslipidemia Mol. Endocrinol., June 1, 2005; 19(6): 1593 - 1605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-Y. Lin, Q. Xu, S. Yeh, R.-S. Wang, J. D. Sparks, and C. Chang Insulin and Leptin Resistance With Hyperleptinemia in Mice Lacking Androgen Receptor Diabetes, June 1, 2005; 54(6): 1717 - 1725. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Moesgaard, C. L. Brand, J. Sturis, B. Ahren, M. Wilken, J. Fleckner, R. D. Carr, O. Svendsen, A. J. Hansen, and D. X. Gram Sensory nerve inactivation by resiniferatoxin improves insulin sensitivity in male obese Zucker rats Am J Physiol Endocrinol Metab, June 1, 2005; 288(6): E1137 - E1145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Koh, M. J. Quon, S. H. Han, W.-J. Chung, J. Y. Ahn, Y.-H. Seo, I. S. Choi, and E. K. Shin Additive Beneficial Effects of Fenofibrate Combined With Atorvastatin in the Treatment of Combined Hyperlipidemia J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1649 - 1653. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Heijboer, E. Donga, P. J. Voshol, Z.-C. Dang, L. M. Havekes, J. A. Romijn, and E. P. M. Corssmit Sixteen hours of fasting differentially affects hepatic and muscle insulin sensitivity in mice J. Lipid Res., March 1, 2005; 46(3): 582 - 588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Murase, S. Haramizu, A. Shimotoyodome, A. Nagasawa, and I. Tokimitsu Green tea extract improves endurance capacity and increases muscle lipid oxidation in mice Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2005; 288(3): R708 - R715. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. V. Erbe, S. Wang, Y.-L. Zhang, K. Harding, L. Kung, M. Tam, L. Stolz, Y. Xing, S. Furey, A. Qadri, et al. Ertiprotafib Improves Glycemic Control and Lowers Lipids via Multiple Mechanisms Mol. Pharmacol., January 1, 2005; 67(1): 69 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Li and C. K. Glass PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis J. Lipid Res., December 1, 2004; 45(12): 2161 - 2173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. T. Villareal and J. O. Holloszy Effect of DHEA on Abdominal Fat and Insulin Action in Elderly Women and Men: A Randomized Controlled Trial JAMA, November 10, 2004; 292(18): 2243 - 2248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
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B. D. Hegarty, S. M. Furler, N. D. Oakes, E. W. Kraegen, and G. J. Cooney Peroxisome Proliferator-Activated Receptor (PPAR) Activation Induces Tissue-Specific Effects on Fatty Acid Uptake and Metabolism in Vivo--A Study Using the Novel PPAR{alpha}/{gamma} Agonist Tesaglitazar Endocrinology, July 1, 2004; 145(7): 3158 - 3164. [Abstract] [Full Text] [PDF]
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B. Desvergne, L. Michalik, and W. Wahli Be Fit or Be Sick: Peroxisome Proliferator-Activated Receptors Are Down the Road Mol. Endocrinol., June 1, 2004; 18(6): 1321 - 1332. [Abstract] [Full Text] [PDF]
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A. J. Davidoff, M. M. Mason, M. B. Davidson, M. W. Carmody, K. K. Hintz, L. E. Wold, D. A. Podolin, and J. Ren Sucrose-induced cardiomyocyte dysfunction is both preventable and reversible with clinically relevant treatments Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E718 - E724. [Abstract] [Full Text] [PDF]
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M. Haluzik, O. Gavrilova, and D. LeRoith Peroxisome Proliferator-Activated Receptor-{alpha} Deficiency Does Not Alter Insulin Sensitivity in Mice Maintained on Regular or High-Fat Diet: Hyperinsulinemic-Euglycemic Clamp Studies Endocrinology, April 1, 2004; 145(4): 1662 - 1667. [Abstract] [Full Text] [PDF]
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J. Zhang, D. I. W. Phillips, C. Wang, and C. D. Byrne Human skeletal muscle PPAR{alpha} expression correlates with fat metabolism gene expression but not BMI or insulin sensitivity Am J Physiol Endocrinol Metab, February 1, 2004; 286(2): E168 - E175. [Abstract] [Full Text] [PDF]
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P. Ferre The Biology of Peroxisome Proliferator-Activated Receptors: Relationship With Lipid Metabolism and Insulin Sensitivity Diabetes, February 1, 2004; 53(90001): S43 - 50. [Abstract] [Full Text]
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M. C. Sugden and M. J. Holness Potential Role of Peroxisome Proliferator-Activated Receptor-{alpha} in the Modulation of Glucose-Stimulated Insulin Secretion Diabetes, February 1, 2004; 53(90001): S71 - 81. [Abstract] [Full Text]
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P. J. Larsen, P. B. Jensen, R. V. Sorensen, L. K. Larsen, N. Vrang, E. M. Wulff, and K. Wassermann Differential Influences of Peroxisome Proliferator-Activated Receptors{gamma} and -{alpha} on Food Intake and Energy Homeostasis Diabetes, September 1, 2003; 52(9): 2249 - 2259. [Abstract] [Full Text] [PDF]
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E. H. Koh, M.-S. Kim, J.-Y. Park, H. S. Kim, J.-Y. Youn, H.-S. Park, J. H. Youn, and K.-U. Lee Peroxisome Proliferator-Activated Receptor (PPAR)-{alpha} Activation Prevents Diabetes in OLETF Rats: Comparison With PPAR-{gamma} Activation Diabetes, September 1, 2003; 52(9): 2331 - 2337. [Abstract] [Full Text] [PDF]
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H. Kim, M. Haluzik, Z. Asghar, D. Yau, J. W. Joseph, A. M. Fernandez, M. L. Reitman, S. Yakar, B. Stannard, L. Heron-Milhavet, et al. Peroxisome Proliferator-Activated Receptor-{alpha} Agonist Treatment in a Transgenic Model of Type 2 Diabetes Reverses the Lipotoxic State and Improves Glucose Homeostasis Diabetes, July 1, 2003; 52(7): 1770 - 1778. [Abstract] [Full Text] [PDF]
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K. Yajima, H. Hirose, H. Fujita, Y. Seto, H. Fujita, K. Ukeda, K. Miyashita, T. Kawai, Y. Yamamoto, T. Ogawa, et al. Combination therapy with PPARgamma and PPARalpha agonists increases glucose-stimulated insulin secretion in db/db mice Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E966 - E971. [Abstract] [Full Text] [PDF]
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C. L. Brand, J. Sturis, C. F. Gotfredsen, J. Fleckner, C. Fledelius, B. F. Hansen, B. Andersen, J.-M. Ye, P. Sauerberg, and K. Wassermann Dual PPARalpha /gamma activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats Am J Physiol Endocrinol Metab, April 1, 2003; 284(4): E841 - E854. [Abstract] [Full Text] [PDF]
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J.-M. Ye, M. A. Iglesias, D. G. Watson, B. Ellis, L. Wood, P. B. Jensen, R. V. Sorensen, P. J. Larsen, G. J. Cooney, K. Wassermann, et al. PPARalpha /gamma ragaglitazar eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly Am J Physiol Endocrinol Metab, March 1, 2003; 284(3): E531 - E540. [Abstract] [Full Text] [PDF]
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T. Nakatani, H.-J. Kim, Y. Kaburagi, K. Yasuda, and O. Ezaki A low fish oil inhibits SREBP-1 proteolytic cascade, while a high-fish-oil feeding decreases SREBP-1 mRNA in mice liver: relationship to anti-obesity J. Lipid Res., February 1, 2003; 44(2): 369 - 379. [Abstract] [Full Text] [PDF]
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I. Pineda Torra, T. Claudel, C. Duval, V. Kosykh, J.-C. Fruchart, and B. Staels Bile Acids Induce the Expression of the Human Peroxisome Proliferator-Activated Receptor {alpha} Gene via Activation of the Farnesoid X Receptor Mol. Endocrinol., February 1, 2003; 17(2): 259 - 272. [Abstract] [Full Text] [PDF]
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M. Gilbert, C. Magnan, S. Turban, J. Andre, and M. Guerre-Millo Leptin Receptor-Deficient Obese Zucker Rats Reduce Their Food Intake in Response to a Systemic Supply of Calories From Glucose Diabetes, February 1, 2003; 52(2): 277 - 282. [Abstract] [Full Text] [PDF]
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M. C. Sugden, G. K. Greenwood, N. D. Smith, and M. J. Holness Peroxisome Proliferator-Activated Receptor-{alpha} Activation during Pregnancy Attenuates Glucose-Stimulated Insulin Hypersecretion in Vivo by Increasing Insulin Sensitivity, without Impairing Pregnancy-Induced Increases in {beta}-Cell Glucose Sensing and Responsiveness Endocrinology, January 1, 2003; 144(1): 146 - 153. [Abstract] [Full Text] [PDF]
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J. Xu, G. Xiao, C. Trujillo, V. Chang, L. Blanco, S. B. Joseph, S. Bassilian, M. F. Saad, P. Tontonoz, W. N. P. Lee, et al. Peroxisome Proliferator-activated Receptor alpha (PPARalpha ) Influences Substrate Utilization for Hepatic Glucose Production J. Biol. Chem., December 20, 2002; 277(52): 50237 - 50244. [Abstract] [Full Text] [PDF]
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H. Duez, Y.-S. Chao, M. Hernandez, G. Torpier, P. Poulain, S. Mundt, Z. Mallat, E. Teissier, C. A. Burton, A. Tedgui, et al. Reduction of Atherosclerosis by the Peroxisome Proliferator-activated Receptor alpha Agonist Fenofibrate in Mice J. Biol. Chem., December 6, 2002; 277(50): 48051 - 48057. [Abstract] [Full Text] [PDF]
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B. Ljung, K. Bamberg, B. Dahllof, A. Kjellstedt, N. D. Oakes, J. Ostling, L. Svensson, and G. Camejo AZ 242, a novel PPAR{alpha}/{gamma} agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats J. Lipid Res., November 1, 2002; 43(11): 1855 - 1863. [Abstract] [Full Text] [PDF]
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E. Aasum, D. D. Belke, D. L. Severson, R. A. Riemersma, M. Cooper, M. Andreassen, and T. S. Larsen Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-alpha activator Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H949 - H957. [Abstract] [Full Text] [PDF]
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C. J. Chou, M. Haluzik, C. Gregory, K. R. Dietz, C. Vinson, O. Gavrilova, and M. L. Reitman WY14,643, a Peroxisome Proliferator-activated Receptor alpha (PPARalpha ) Agonist, Improves Hepatic and Muscle Steatosis and Reverses Insulin Resistance in Lipoatrophic A-ZIP/F-1 Mice J. Biol. Chem., June 28, 2002; 277(27): 24484 - 24489. [Abstract] [Full Text] [PDF]
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L. Madsen, M. Guerre-Millo, E. N. Flindt, K. Berge, K. J. Tronstad, E. Bergene, E. Sebokova, A. C. Rustan, J. Jensen, S. Mandrup, et al. Tetradecylthioacetic acid prevents high fat diet induced adiposity and insulin resistance J. Lipid Res., May 1, 2002; 43(5): 742 - 750. [Abstract] [Full Text] [PDF]
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I. Pineda Torra, Y. Jamshidi, D. M. Flavell, J.-C. Fruchart, and B. Staels Characterization of the Human PPAR{alpha} Promoter: Identification of a Functional Nuclear Receptor Response Element Mol. Endocrinol., May 1, 2002; 16(5): 1013 - 1028. [Abstract] [Full Text] [PDF]
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O. Barbier, I. P. Torra, Y. Duguay, C. Blanquart, J.-C. Fruchart, C. Glineur, and B. Staels Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors in Lipid Metabolism and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., May 1, 2002; 22(5): 717 - 726. [Abstract] [Full Text] [PDF]
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D. M. Muoio, J. M. Way, C. J. Tanner, D. A. Winegar, S. A. Kliewer, J. A. Houmard, W. E. Kraus, and G. L. Dohm Peroxisome Proliferator-Activated Receptor-{alpha} Regulates Fatty Acid Utilization in Primary Human Skeletal Muscle Cells Diabetes, April 1, 2002; 51(4): 901 - 909. [Abstract] [Full Text] [PDF]
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G. J. Etgen, B. A. Oldham, W. T. Johnson, C. L. Broderick, C. R. Montrose, J. T. Brozinick, E. A. Misener, J. S. Bean, W. R. Bensch, D. A. Brooks, et al. A Tailored Therapy for the Metabolic Syndrome : The Dual Peroxisome Proliferator-Activated Receptor-{alpha}/{gamma} Agonist LY465608 Ameliorates Insulin Resistance and Diabetic Hyperglycemia While Improving Cardiovascular Risk Factors in Preclinical Models Diabetes, April 1, 2002; 51(4): 1083 - 1087. [Abstract] [Full Text] [PDF]
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D. B. Jump The Biochemistry of n-3 Polyunsaturated Fatty Acids J. Biol. Chem., March 8, 2002; 277(11): 8755 - 8758. [Full Text] [PDF]
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J. R. Levy, B. Davenport, J. N. Clore, and W. Stevens Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats Am J Physiol Endocrinol Metab, March 1, 2002; 282(3): E626 - E633. [Abstract] [Full Text] [PDF]
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F. M. Campbell, R. Kozak, A. Wagner, J. Y. Altarejos, J. R. B. Dyck, D. D. Belke, D. L. Severson, D. P. Kelly, and G. D. Lopaschuk A Role for Peroxisome Proliferator-activated Receptor alpha (PPARalpha ) in the Control of Cardiac Malonyl-CoA Levels. REDUCED FATTY ACID OXIDATION RATES AND INCREASED GLUCOSE OXIDATION RATES IN THE HEARTS OF MICE LACKING PPARalpha ARE ASSOCIATED WITH HIGHER CONCENTRATIONS OF MALONYL-CoA AND REDUCED EXPRESSION OF MALONYL-CoA DECARBOXYLASE J. Biol. Chem., February 1, 2002; 277(6): 4098 - 4103. [Abstract] [Full Text] [PDF]
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M. Guerre-Millo, C. Rouault, P. Poulain, J. Andre, V. Poitout, J. M. Peters, F. J. Gonzalez, J.-C. Fruchart, G. Reach, and B. Staels PPAR-{alpha}-Null Mice Are Protected From High-Fat Diet-Induced Insulin Resistance Diabetes, December 1, 2001; 50(12): 2809 - 2814. [Abstract] [Full Text] [PDF]
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P.-M. Chao, C.-Y. Chao, F.-J. Lin, and C.-j. Huang Oxidized Frying Oil Up-Regulates Hepatic Acyl-CoA Oxidase and Cytochrome P450 4 A1 Genes in Rats and Activates PPAR{alpha} J. Nutr., December 1, 2001; 131(12): 3166 - 3174. [Abstract] [Full Text] [PDF]
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D. A. Winegar, P. J. Brown, W. O. Wilkison, M. C. Lewis, R. J. Ott, W. Q. Tong, H. R. Brown, J. M. Lehmann, S. A. Kliewer, K. D. Plunket, et al. Effects of fenofibrate on lipid parameters in obese rhesus monkeys J. Lipid Res., October 1, 2001; 42(10): 1543 - 1551. [Abstract] [Full Text] [PDF]
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A. Cabrero, M. Alegret, R. M. Sanchez, T. Adzet, J. C. Laguna, and M. Vazquez Bezafibrate Reduces mRNA Levels of Adipocyte Markers and Increases Fatty Acid Oxidation in Primary Culture of Adipocytes Diabetes, August 1, 2001; 50(8): 1883 - 1890. [Abstract] [Full Text] [PDF]
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J.-M. Ye, P. J. Doyle, M. A. Iglesias, D. G. Watson, G. J. Cooney, and E. W. Kraegen Peroxisome Proliferator--Activated Receptor (PPAR)-{alpha} Activation Lowers Muscle Lipids and Improves Insulin Sensitivity in High Fat--Fed Rats: Comparison With PPAR-{gamma} Activation Diabetes, February 1, 2001; 50(2): 411 - 417. [Abstract] [Full Text]
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M. J. Barbera, A. Schluter, N. Pedraza, R. Iglesias, F. Villarroya, and M. Giralt Peroxisome Proliferator-activated Receptor alpha Activates Transcription of the Brown Fat Uncoupling Protein-1 Gene. A LINK BETWEEN REGULATION OF THE THERMOGENIC AND LIPID OXIDATION PATHWAYS IN THE BROWN FAT CELL J. Biol. Chem., January 5, 2001; 276(2): 1486 - 1493. [Abstract] [Full Text] [PDF]
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J.-H. Kim, T. M. Lewin, and R. A. Coleman Expression and Characterization of Recombinant Rat Acyl-CoA Synthetases 1, 4, and 5. SELECTIVE INHIBITION BY TRIACSIN C AND THIAZOLIDINEDIONES J. Biol. Chem., June 29, 2001; 276(27): 24667 - 24673. [Abstract] [Full Text] [PDF]
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T. Yamauchi, J. Kamon, H. Waki, K. Murakami, K. Motojima, K. Komeda, T. Ide, N. Kubota, Y. Terauchi, K. Tobe, et al. The Mechanisms by Which Both Heterozygous Peroxisome Proliferator-activated Receptor gamma (PPARgamma ) Deficiency and PPARgamma Agonist Improve Insulin Resistance J. Biol. Chem., October 26, 2001; 276(44): 41245 - 41254. [Abstract] [Full Text] [PDF]
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Y. Nagai, Y. Nishio, T. Nakamura, H. Maegawa, R. Kikkawa, and A. Kashiwagi Amelioration of high fructose-induced metabolic derangements by activation of PPARalpha Am J Physiol Endocrinol Metab, May 1, 2002; 282(5): E1180 - E1190. [Abstract] [Full Text] [PDF]
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