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Am J Physiol Endocrinol Metab 290: E607-E611, 2006. First published November 8, 2005; doi:10.1152/ajpendo.00430.2005
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PPAR{delta} activator GW-501516 has no acute effect on glucose transport in skeletal muscle

Shin Terada, Scott Wicke, John O. Holloszy, and Dong-Ho Han

Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri

Submitted 7 September 2005 ; accepted in final form 1 November 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
It has been reported that treatment of cultured human skeletal muscle myotubes with the peroxisome proliferator-activated receptor-{delta} (PPAR{delta}) activator GW-501516 directly stimulates glucose transport and enhances insulin action. Cultured myotubes are minimally responsive to insulin stimulation of glucose transport and are not a good model for studying skeletal muscle glucose transport. The purpose of this study was to evaluate the effect of GW-501516 on glucose transport to determine whether the findings on cultured myotubes have relevance to skeletal muscle. Rat epitrochlearis and soleus muscles were treated for 6 h with 10, 100, or 500 nM GW-501516, followed by measurement of 2-deoxyglucose uptake. GW-501516 had no effect on glucose uptake. There was no effect on insulin sensitivity or responsiveness. Also, in contrast to findings on myotubes, treatment of muscles with GW-501516 did not result in increased phosphorylation or increased expression of AMP-activated protein kinase (AMPK) or p38 mitogen-activated protein kinase (MAPK). Treatment of epitrochlearis muscles with GW-501516 for 24 h induced a threefold increase in uncoupling protein-3 mRNA, providing evidence that the GW-501516 compound that we used gets into and is active in skeletal muscle. In conclusion, our results show that, in contrast to myotubes in culture, skeletal muscle does not respond to GW-501516 with 1) an increase in AMPK or p38 MAPK phosphorylation or expression or 2) direct stimulation of glucose transport or enhanced insulin action.

peroxisome proliferator-activated receptor-{delta}; adenosine monophosphate-activated protein kinase; p38 mitogen-activated protein kinase; insulin; uncoupling protein-3

THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-{delta} (PPAR{delta}) is a nuclear receptor that regulates expression of genes encoding the uncoupling proteins (UCPs) and enzymes involved in the transport and oxidation of fatty acids (12–15). PPAR{delta} is activated by various fatty acids and fatty acid derivatives (2). It also binds to and is activated by PPAR{gamma} coactivator-1{alpha} (PGC-1{alpha}) (14). PGC-1{alpha} is a coactivator of the transcription factors that regulate mitochondrial biogenesis. In addition to increasing the capacity for fat oxidation, pharmacological activation or transgenic overexpression of PPAR{delta} induces an increase in mitochondrial biogenesis in skeletal muscle (12, 13, 15) with conversion of white muscle fibers to red fibers (12, 15). This adaptation resembles that induced by endurance exercise training (1, 7) or by the overexpression of PGC-1{alpha} (10). How this adaptive response is mediated is currently a mystery because, in addition to the expected increases in mitochondrial fatty acid oxidation enzymes and UCPs, it involves increased expression of a wide range of mitochondrial and other proteins encoded in genes that do not have PPAR{delta} binding sites in their promoters.

The biological effects induced by the pharmacological activation or transgenic overexpression of PPAR{delta} have been reported to include protection against obesity and insulin resistance, increased expression of the GLUT4 glucose transporter in muscles, and improvements in insulin action and glucose tolerance (12–15). Recently Krämer et al. (9) reported that treatment of cultured primary human skeletal muscle, or C2C12, myotubes with the PPAR{delta} activator GW-501516 for 6 h increases AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK) phosphorylation and expression, directly stimulates glucose transport, and enhances insulin-stimulated glucose transport. Those authors suggested that these acute effects of GW-501516 provide biological validation of PPAR{delta} as a potential target for antidiabetic therapy. PPAR{delta} activators may well turn out to be useful in antidiabetic therapy. However, cultured myotubes, which resemble fetal muscle, are minimally responsive to insulin stimulation of glucose transport and are not a suitable model for studying regulation of glucose transport in skeletal muscle (8). Therefore, the interesting findings of Krämer et al. cannot be extrapolated, or assumed to have relevance, to skeletal muscle. In this context, the purpose of the present study was to determine whether or not the PPAR{delta} activator GW-501516 stimulates glucose transport in skeletal muscle.


   MATERIALS AND METHODS
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 MATERIALS AND METHODS
RESULTS
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Materials. 2-Deoxy-[1,2-3H]glucose (2-DG) was purchased from American Radiolabeled Chemicals (St. Louis, MO). [14C]mannitol was obtained from ICN Radiochemicals (Irvine, CA). GW-501516 was purchased from Calbiochem (San Diego, CA). Purified pork insulin was purchased from Eli Lilly (Indianapolis, IN). A polyclonal antibody specific for the GLUT4 glucose transporter was the generous gift of Dr. Mike Mueckler (Washington University, St. Louis, MO). Anti-phospho-(Thr180/Tyr182) p38 MAPK, total p38 MAPK, anti-phospho-(Thr172) AMPK, and total AMPK antibodies were purchased from Cell Signaling (Beverly, MA). Horseradish peroxidase (HRP)-conjugated donkey anti-rabbit IgG was purchased from Jackson ImmunoResearch Laboratories (West Grove, PA). Enhanced chemiluminescence (ECL) reagents were obtained from Amersham (Arlington Heights, IL). All other chemicals were obtained from Sigma (St. Louis, MO).

Animal care and muscle preparations. Male Wistar rats (Charles River Laboratories, Wilmington, MA) weighing 80–120 g were provided with Purina Rat Chow and water ad libitum. At 5:00 PM the evening before the experiment, food was removed. An intraperitoneal injection of pentobarbital sodium (5 mg/100 g body wt) was used to anesthetize the rats, followed by the removal of the epitrochlearis and soleus muscles. The epitrochlearis, a small, thin muscle of the forelimb, is well suited for studies of glucose transport. Soleus muscles were split longitudinally into strips before incubation, as described previously (6), to allow adequate diffusion of oxygen and substrates. All procedures were approved by the Animal Studies Committee of Washington University.

Muscle incubations. After dissection, epitrochlearis and soleus muscles were incubated with shaking at 35°C in flasks containing 2 ml of oxygenated Krebs-Henseleit bicarbonate buffer (KHB; containing 8 mM glucose, 32 mM mannitol, and 0.1% radioimmunoassay-grade BSA) or in the same medium with 10, 100, and 500 nM GW-501516 for 6 h. The medium was replaced with fresh medium after 3 h. The gas phase in the flasks was 95% O2-5% CO2. Because GW-501516 is light sensitive, flasks containing this compound were wrapped in foil.

Measurement of glucose transport activity. To remove glucose from the extracellular space, the muscles were rinsed for 30 min at 29°C in 2 ml of oxygenated KHB containing 2 mM sodium pyruvate, 36 mM mannitol, and GW-501516 if it was present during the previous incubation. After the rinse step, muscles were incubated for 20 min at 29°C in 2 ml of KHB containing 4 mM [1,2-3H]2-DG (1.5 µCi/ml) and 36 mM [14C]mannitol (0.2 µCi/ml) with a gas phase of 95% O2-5% CO2 in a shaking incubator. The same additions that were in the rinse step were present during the determination of glucose transport. The muscles were then blotted and clamp-frozen and processed for determination of intracellular 2-DG accumulation and extracellular space, as described previously (18).

AMPK and p38 MAPK phosphorylation and total protein. After incubation for 6 h in the presence or absence of 10 nM GW-501516, as described above, or after being simulated to contract as described previously (17), epitrochlearis muscles were used for measurement of phosphorylation status of AMPK and p38 MAPK. Clamp-frozen epitrochlearis muscles were homogenized in a 30:1 ratio of ice-cold buffer containing 50 mM Tris·HCl (pH 7.4), 1% NP-40, 0.25% sodium deoxycholate, 150 mM NaCl, 1 mM Pefabloc, 1 mM each of EDTA and NaF, 1 µg/ml each of aprotinin, leupeptin, and pepstatin, 0.1 mM bpV(phen), and 2 mg/ml beta-glycerophosphate. Protein concentration was determined by the method of Lowry et al. (11). Samples were prepared in 2x Laemmli sample buffer containing 100 nM dithiothreitol and heated in a boiling water bath for 5 min. Next, 60 µg of protein from each sample were subjected to SDS-PAGE (10% resolving gel) and then transferred to nitrocellulose membranes at 200 mA for 1 h. After transfer, membranes were blocked for 1 h at room temperature in Tris-buffered saline with 0.1% Tween (TBST; 200 mM Tris base, 1.37 M NaCl, pH 7.4) supplemented with 5% nonfat dry milk. Membranes were incubated overnight at 4°C with antibodies specific for phosphorylated p38 MAPK (Thr180/Tyr182), phosphorylated AMPK (Thr172), total p38 MAPK, and total AMPK at concentrations of 1:1,000–2,500. The HRP-conjugated secondary antibody (donkey anti-rabbit IgG) was used at a concentration of 1:5,000. Bands were visualized by ECL and quantified using densitometry.

Prolonged muscle incubations. Epitrochlearis muscles were incubated in tissue culture medium in the presence or absence of 500 nM GW-501516 in flasks in a shaking incubator maintained at 35°C. The vials, containing 2 ml of medium, were gassed continuously with 95% O2-5% CO2 throughout the incubation. The incubation medium consisted of {alpha}-MEM (GIBCO-BRL 1200-063), 10% fetal bovine serum, 50 µU/ml purified pork insulin, 1% BSA, 5 mM mannitol, 2.54 mM CaCl2, 2.2 g/l sodium bicarbonate, 100 µU/ml penicillin, and 100 µg/ml streptomycin. The medium was sterilized by filtration through 0.2-µm Millipore filters. The medium was replaced with fresh medium every 6 h. After a 24-h-long incubation period, the muscles were washed in 2 ml of PBS for 10 min, blotted, clamp-frozen, and stored at –80°C until they were used for measurement of GLUT4 protein and UCP3 mRNA. The GLUT4 protein content was determined by Western blotting as described previously (3).

Semiquantitative RT-PCR. PPAR{delta} has been shown to regulate UCP3 gene expression in skeletal muscle (13, 15). UCP3 mRNA was measured to evaluate the bioactivity of GW-501516 in this study in rat skeletal muscle. Total RNA from epitrochlearis muscle was isolated using TRIzol reagent (Invitrogen). Because the RNA extraction procedure required a larger amount of tissue, two epitrochlearis muscles were homogenized together. The DNase-treated total RNA (1 µg) was reverse transcribed (RT) into cDNA by using random primer and Im Prom-II Reverse Transcriptase (Promega, Madison, WI). Aliquots of each RT reaction were added to a PCR master mix (Promega) mixture containing Taq DNA polymerase, dNTPs, MgCl2, reaction buffers at optimal concentrations for efficient amplification of DNA templates by PCR, and 10 pmol of both sense and antisense primers (forward 5'-GTACGGTCATCATCTGACAC-3', reverse 5'-GGTGAGTATCTGCATATGAT-3'). The reaction medium was subjected to PCR amplification. After the lid was warmed at 94°C for 2 min, the PCR mixtures were subjected to a 27-cycle profile, including denaturation for 30 s at 94°C, hybridization for 60 s at 58°C, and elongation for 60 s at 72°C. In the present investigation, 18S rRNA expression was simultaneously measured as an internal standard by using a QuantumRNA 18S Internal Standard Kit (Ambion, Austin, TX). The PCR products were separated by electrophoresis on 2% agarose, stained with SYBR Green (Molecular Probes, Eugene, OR), photographed, and analyzed by densitometry. The ratio of UCP3 to 18S rRNA standard band densities was then calculated.

Statistical analysis. Results are expressed as means ± SE. The significance of differences between two groups was assessed using Student's t-test. For multiple comparisons, significance was determined by one-way analysis of variance followed by a post hoc comparison using Tukey significant difference method.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
AMPK and p38 MAPK phosphorylation. Krämer et al. (9) reported that treatment of human myotubes with 10 nM GW-501516 for 6 h resulted in increased phosphorylation of AMPK and p38 MAPK. Either of these events could mediate an increase in muscle glucose transport (4, 5, 16). In contrast to the response of human skeletal muscle myotubes in culture (9), incubation of rat epitrochlearis muscles with GW-501516 for 6 h had no effect on phosphorylation of AMPK or p38 MAPK (Fig. 1 and Fig. 2). Expression of AMPK and p38 MAPK proteins was also unaffected (Fig. 1 and Fig. 2). Muscles that were stimulated to contract were included as a positive control.


Figure 1
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  		Fig. 1. Peroxisome proliferator-activated receptor-{delta} (PPAR{delta}) activator GW-501516 does not increase AMP-activated protein kinase (AMPK) phosphorylation or expression in skeletal muscle. Some epitrochlearis muscles were incubated with or without 10 nM GW-501516 for 6 h; other muscles were stimulated to produce ten 10-s-long tetanic contractions. Homogenates of clamp-frozen muscles were used for measurement of phospho-AMPK and total AMPK. Values are means ± SE for 6 muscles per group.

 

Figure 2
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  		Fig. 2. GW-501516 does not increase p38 mitogen-activated protein kinase (MAPK) phosphorylation or expression in skeletal muscle. Some epitrochlearis muscles were incubated with or without 10 nM GW-501516 for 6 h; other muscles were stimulated to contract. Homogenates of clamp-frozen muscles were used for measurement of phospho-p38 MAPK and total p38 MAPK. Values are means ± SE for 6 muscles per group.

 
Glucose transport activity. Krämer et al. (9) found that treatment of cultured primary human myotubes or C2C12 myotubes with 10 nM of the specific PPAR{delta} activator GW-501516 for 6 h led to a modest (~30%) increase in glucose transport activity. To determine whether GW-501516 also activates glucose transport in skeletal muscle, we incubated rat epitrochlearis and soleus muscles with 10 nM GW-501516 for 6 h. As shown in Fig. 3, GW-501516 had no effect on 2-DG transport into either the epitrochlearis or soleus muscle. Incubation with higher concentrations, 100 nM or 500 nM, also had no effect on glucose transport activity in epitrochlearis or soleus muscles.


Figure 3
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  		Fig. 3. GW-501516 treatment does not increase glucose transport activity in skeletal muscle. Epitrochlearis (A) and soleus muscles (B) were incubated in the presence or absence of 10, 100, or 500 nM GW-501516 for 6 h, followed by measurement of 2-deoxyglucose (2-DG) transport. Values are means ± SE for 7 muscles per group.

 
Interaction with insulin. Incubation of epitrochlearis and soleus muscles with GW-501516 for 6 h had no effect on insulin sensitivity or insulin responsiveness of glucose transport (Fig. 4).


Figure 4
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  		Fig. 4. Submaximally and maximally insulin-stimulated 2-DG transport in epitrochlearis (A) and soleus muscles (B) after 6-h exposure to 10 nM GW-501516. Values are means ± SE for 6 muscles per group.

 
GLUT4 protein content. Tanaka et al. (13) have reported that oral administration of GW-501516 to mice for 7 days induced a significant increase in GLUT4 mRNA in skeletal muscle. Incubation of epitrochlearis in culture medium containing 500 nM GW-501516 had no effect on GLUT4 protein expression (data not shown), providing evidence that this adaptive response takes longer than 24 h to develop.

UCP3 mRNA. In view of our negative results, we became concerned that the GW-501516 compound that we were using was either not biologically active or was not getting into our muscle preparation. We therefore examined the effect of 24 h of incubation of epitrochlearis muscles with 500 nM GW-501516 on UCP3 mRNA abundance. UCP3 gene expression is regulated by PPAR{delta} (13–15). As shown in Fig. 5, GW-501516 treatment increased epitrochlearis muscle UCP3 mRNA content threefold, providing evidence that GW-501516 enters, and is biologically active in, our muscle preparation.


Figure 5
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  		Fig. 5. GW-501516 increased uncoupling protein-3 (UCP3) mRNA in skeletal muscle. Epitrochlearis muscles were incubated with or without 500 nM GW-501516 for 24 h. After incubation, muscles were clamp-frozen for semiquantitative RT-PCR analysis. Values represent means ± SE for 5 muscles. *P < 0.05 vs. basal group.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Transgenic expression of activated PPAR{delta} in adipocytes leads to a lean phenotype and prevents high-fat diet-induced obesity in mice by increasing energy expenditure and fat oxidation (14). These effects appear to be due to increased thermogenesis and fat oxidation as a result of increased expression of UCP1 in brown adipose tissue, induction of UCP1 expression in white adipose tissue, and increased expression of mitochondrial enzymes of fatty acidation (14).

Transgenic overexpression of PPAR{delta} in skeletal muscle results in increased mitochondrial biogenesis and an increase in the proportion of oxidative fibers (12, 15) and also protects against obesity (12, 15) and insulin resistance (15). The mechanism for this protective effect is not clear but could involve increased resting thermogenesis. Similar adaptive responses and protection against obesity and insulin resistance are seen in mice treated with the PPAR{delta} activator GW-501516 (13).

Krämer et al. (9) have reported that treatment of cultured myotubes for 6 h with GW-501516 results in both increased expression and phosphorylation of AMPK and p38 MAPK. It is not known whether increases in expression of AMPK and/or p38 MAPK are a component of the adaptive response induced by activation of PPAR{delta}, as they were not included among the enzymes measured in previous studies of the effect of PPAR{delta} activation. However, it seems unlikely that activation of a nuclear receptor would result in phosphorylation of these proteins, raising the possibility that GW-501516 activates these enzymes by another mechanism. Our finding that GW-501516 treatment had no effect on AMPK or p38 MAPK expression or phosphorylation in epitrochlearis or soleus muscles argues against this possibility. Similarly, it is not clear whether the ~30% increase in glucose transport activity observed in response to GW-501516 in cultured myotubes was a direct effect of the GW-501516 preparation used or was somehow mediated by PPAR{delta}. Our finding that the same, or many-fold higher, concentrations of GW-501516 had no effect on glucose transport activity in rat epitrochlearis or soleus muscles makes it unlikely that the findings on cultured myotubes have relevance to adult skeletal muscle.

In conclusion, although available evidence suggests that PPAR{delta} activators may have great potential as anti-obesity and anti-insulin resistance agents, it seems unlikely that activation of glucose transport in skeletal muscle is among their mechanisms of action.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This research was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-18986. S. Terada was supported by a Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists.


   ACKNOWLEDGMENTS
 
We thank Victoria Reckamp for expert assistance with preparation of the manuscript.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D.-H. Han, Washington Univ. School of Medicine, 4566 Scott Ave., Campus Box 8113, St. Louis, MO 63110 (e-mail: dhan{at}im.wustl.edu)

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.


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 RESULTS
 DISCUSSION
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