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Endocrinology Vol. 139, No. 3 832-837
Copyright © 1998 by The Endocrine Society

ARTICLES

Troglitazone Increases System A Amino Acid Transport in 3T3-L1 Cells

Ti-Zhi Su, Minghan Wang, Dale L. Oxender and Alan R. Saltiel

Departments of Molecular Biology (T.-Z.S., M.W.) and Cell Biology (D.L.O., A.R.S.), Parke-Davis Pharmaceutical Research Division of Warner Lambert Co., Ann Arbor, Michigan 48105

Address all correspondence and requests for reprints to: Dr. Ti-Zhi Su, Department of Molecular Biology, Parke-Davis Pharmaceutical Research Division of Warner Lambert Co., 2800 Plymouth Road, Ann Arbor, Michigan 48105. E-mail: sut{at}aa.wl.com


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
System A is one of the most highly regulated transport systems for transport of neutral amino acids into mammalian cells. Stimulation of uptake of {alpha}-[3H]methylaminoisobutyric acid (MeAIB), a nonmetabolizable system A substrate, by a novel insulin-sensitizing agent, troglitazone, in 3T3-L1 adipocytes was investigated. Treating adipocytes with troglitazone alone resulted in a time- and dose-dependent increase in the uptake of MeAIB. The peak stimulation appeared about 24 h after troglitazone addition. Both troglitazone- and insulin-stimulated transport activities increased markedly after the induction of differentiation of preadipocytes into adipocytes, and declined to a steady state level in adipocytes. The stimulated MeAIB uptake exhibited substrate specificity typical of system A and was mediated by a single component as determined by Eadie-Hofstee plots. The stimulation by troglitazone and that by insulin were similarly sensitive to actinomycin D and cycloheximide, suggesting that both agents may induce de novo synthesis of the same type of system A transport. Apart from the insulin-independent effect, troglitazone also showed an insulin-dependent action characterized by enhanced sensitivity to insulin. The synergistic stimulation of MeAIB uptake by coadministration of insulin and troglitazone was most prominent at the early stages of adipocyte differentiation. Pretreating cells with troglitazone during the differentiation attenuated the sensitivity of insulin to inhibition by actinomycin D, suggesting that troglitazone may enhance the insulin action by stabilizing messenger RNA involved in system A function.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ONE of the most important actions of insulin is to control amino acid transport in fat, liver, and muscle cells. This effect of the hormone is mainly due to the regulation of system A, a highly concentrative and sodium-dependent system that primarily mediates the uptake of neutral amino acids with short, polar, or linear side-chains (1, 2). Among these amino acids are important gluconeogenic amino acids such as alanine, glutamine, threonine, serine, and glycine.

Troglitazone is a member of the thiazolidinedione (TZD) class of compounds. These molecules improve both hepatic and peripheral insulin action in a variety of genetic and acquired models of insulin resistance (3). TZDs bind to and activate the peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) (4), resulting in the regulated expression of genes encoding proteins central to carbohydrate and lipid metabolism. PPARs are members of steroid/thyroid/retinoid receptor superfamily. Three major subtypes, PPAR{alpha}, PPAR{gamma}, and PPAR{delta}, have been identified, which vary mainly in their ligand binding specificity and tissue distribution (5). These nuclear receptors heterodimerize with retinoic X receptor and interact with genes involved in intermediary metabolism in fat, liver, and muscle. The binding of TZDs to PPAR{gamma} correlates strongly with many in vivo activities, including adipogenesis (6, 7, 8), terminal differentiation of human liposarcoma cells (9), repression of leptin gene expression (10, 11, 12), activation of lipoprotein lipase (13), and attenuation of hyperglycemia (14, 15).

Although the effect of TZDs on glucose transport is well established (16, 17, 18, 19, 20, 21, 22), little is known about the role of these drugs in regulating amino acid transport. Elevations in circulating amino acids and abnormal metabolism of gluconeogenic amino acids have been observed in models of both type I and type II diabetes (23, 24, 25, 26, 27, 28). However, the link between amino acid transport and the abnormalities of amino acid homeostasis with respect to insulin remains uncertain. We describe here an insulinomimetic and insulin-enhancing effect of troglitazone on system A amino acid transport in 3T3-L1 adipocytes.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Materials
Cell culture reagents were purchased from Life Technologies (Grand Island, NY). [3H]MeAIB (60 Ci/mmol) was purchased from American Radiolabeled Chemicals (St. Louis, MO). Troglitazone was obtained from Parke-Davis. All other chemicals were purchased from Sigma Chemical Co. (St. Louis, MO).

Cell culture
3T3-L1 fibroblasts were maintained in DMEM supplemented with 10% calf serum in an atmosphere of 5% CO2-air. Differentiation to adipocytes was induced by incubating confluent monolayers (day 0) for 2 days in DMEM containing 10% FBS, 0.5 mM 3-isobutyl-1-methylxanthine, and 0.4 µg/ml dexamethasone, followed by incubation for 2 more days in DMEM containing 10% FBS and 1 µg/ml insulin. Two days after transfer to the same medium without insulin, greater than 90% of the cells expressed the adipocyte phenotype. Unless otherwise stated, experiments were performed on adipocytes on days 4–5 after the induction of differentiation.

The cells were washed twice with serum-free DMEM medium and then serum starved for 3 h, followed by switching to the stimulus-containing DMEM. Unless otherwise specified, the cells were incubated with troglitazone and insulin at concentrations of 5 µM and 100 nM, respectively, for 33 h. Decay of the induced transport activity was determined after twice washing cells followed by incubation in Dulbecco’s PBS, consisting of 137 mM NaCl, 2.7 mM KCl, 10.6 mM Na2HPO4, and 1.5 mM KH2PO4. Cells were manipulated in PBS buffer (pH 7.4) supplemented with 20 mM D-glucose, 0.49 mM MgCl2, 0.9 mM CaCl2, and 0.2% BSA (PBS.GMC).

Assay of amino acid transport
The cells were grown in 24-well plates (diameter of well, 1.5 cm) for transport experiments. The sodium-containing buffer for transport assay was PBS.GMC. The cluster tray transport assay was used as described previously (29). To eliminate trans-inhibition, the intracellular pool of amino acids was depleted by incubation in PBS.GMC for 40 min, with a change to fresh PBS at 20 min, in the presence or absence of stimuli. An appropriate amount of choline chloride was added to each reaction mixture to keep all solutions at equal osmolarity. As uptake of MeAIB was linear at 37 C for at least 15 min, 10-min uptake was used for determining initial uptake rates. Unless otherwise noted, the MeAIB concentration for initial rate of transport measurements was 50 µM. All transport rates were referred to as saturable uptake rates, which were calculated by subtracting the labeled MeAIB uptake rates in the presence of 10 mM excess unlabeled MeAIB from the total uptake rates.

Data analysis
The mean induced transport activity ± SD was determined for each assay condition. The data represent typical results, which were confirmed by at least two independent experiments, each performed in triplet. Various assay conditions were compared using Student’s t test, and P < 0.05 was considered statistically significant. The KaleidaGraph (Synergy Software, Reading, PA) curve-fitting program was used for regression analysis.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Troglitazone stimulates MeAIB uptake in 3T3-L1 adipocytes
Our previous studies have demonstrated that insulin induces MeAIB uptake in 3T3-L1 adipocytes via system A (30). In contrast to the regulation of glucose transport by insulin, which is detectable within minutes (20), the stimulation of system A transport by insulin requires several hours before it reaches significant levels, reflecting a transcriptional mechanism (30). To explore the regulation of MeAIB uptake by troglitazone, the cells were incubated with 5 µM troglitazone for up to 80 h. As shown in Fig. 1AGo, prolonged incubation was required to obtain a measurable increase over the basal saturable MeAIB uptake. The maximal approximately 5-fold stimulation of MeAIB uptake by troglitazone (95 ± 6 vs. 19 ± 6 pmol/min·mg protein on day 4; P < 0.001) was generally achieved by 20–30 h, longer than the time required for reaching the peak response observed with insulin (30). Moreover, the increase was sustained for up to 80 h. To evaluate the dose response to troglitazone, the adipocytes were treated with troglitazone at concentrations ranging from 0.05–5 µM for 33 h. The effect of troglitazone was dose dependent, with an EC50 of 240 nM (Fig. 1BGo). The troglitazone effect appeared to be insulin and serum independent, as the cells were sufficiently washed and pretreated with serum- and insulin-free medium for 3 h.



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  		Figure 1. Troglitazone (Tgz)-stimulated MeAIB uptake in 3T3-L1 adipocytes. A, The time course of stimulation of MeAIB uptake by 5 µM troglitazone. The adipocytes on day 5 were serum starved for 3 h and then incubated with troglitazone in serum-free DMEM medium for the times indicated. Before transport assays, the DMEM medium was replaced by PBS.GMC containing troglitazone. Transport assays were carried out as described in Materials and Methods. B, Dose-dependent stimulation of MeAIB uptake by troglitazone. The adipocytes were treated as described in A for 33 h with different concentrations of troglitazone. Curve fitting to a hyperbolic equation was carried out using KaleidaGraph software with r > 0.99. Values are the mean ± SD (n = 3).

 
Stimulation of MeAIB uptake by troglitazone is differentiation dependent
The stimulation of MeAIB uptake by insulin in 3T3-L1 cells depends on differentiation of the cells, and the state of insulin sensitivity increases markedly upon differentiation into adipocytes (30). To assess the impact of differentiation on the capacity of troglitazone to stimulate amino acid transport, 5 µM troglitazone was introduced on various days after the induction of differentiation. Treatment of 3T3-L1 preadipocytes with troglitazone did not significantly increase MeAIB uptake over basal levels (Fig. 2Go). However, 2 days after the induction of differentiation, transport activity increased dramatically in response to troglitazone (143 ± 2 vs. 27 ± 16 pmol/min·mg protein on day 3; P < 0.001). As the cells took on a more adipogenic phenotype, the levels of stimulation decreased to 2- to 3-fold over the basal value (69 ± 5 vs. 22 ± 2 pmol/min·mg protein on day 6; P < 0.001). Interestingly, the differentiation-dependent pattern of the response to troglitazone paralleled that for insulin.



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  		Figure 2. Differentiation-dependent stimulation of MeAIB uptake by troglitazone and insulin in 3T3-L1 cells. At the indicated time after induction of differentiation, the cells were serum starved for 3 h and then incubated in DMEM containing 5 µM troglitazone or/and 100 nM insulin for 23 h. One hour before transport assays, the growth media were replaced by PBS.GMC containing the corresponding stimuli. The transport assays were carried out as described in Materials and Methods. Values are the mean ± SD (n = 4). CTRL, Unstimulated control; Ins, insulin; Tgz, troglitazone.

 
To further compare the effects of troglitazone with those of insulin, we evaluated the effects of the drug when added together with insulin. As shown in Fig. 2Go, the effects of combination treatment varied with the stage of differentiation. At the onset of differentiation, treatment with maximal doses of both troglitazone and insulin increased MeAIB uptake to an extent greater than that predicted from the sum of the effects produced by troglitazone or insulin alone, suggesting that the synergy between troglitazone and insulin is more closely correlated with the onset of adipogenesis. To further characterize the synergy between troglitazone and insulin, the cells on day 4 were pretreated with 5 µM troglitazone for 24 h, deprived of serum for 3 h, and then exposed to various concentrations of insulin for an additional 5 h. Figure 3Go illustrates that troglitazone significantly enhanced the maximal response to insulin by about 2-fold (0.21 ± 0.03 vs. 0.14 ± 0.02 nmol/min·mg protein; P < 0.01) and increased the sensitivity to insulin by approximately 4.2-fold (EC50 = 2.1 ± 0.3 vs. 8.9 ± 1.7 nM; P < 0.01). The existence of both insulin-independent and insulin-dependent stimulation of amino acid transport by troglitazone is consistent with the long term effect of troglitazone on glucose transport (21).



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  		Figure 3. Dose-dependent stimulation of MeAIB uptake by insulin in 3T3-L1 adipocytes. The adipocytes on day 4 after induction of differentiation were pretreated with 5 µM troglitazone for 24 h. The cells were then serum deprived for 3 h in PBS.GMC medium containing troglitazone. Insulin at concentrations ranging from 0.5–174 nM was then added, and the cells were incubated for 5 h. Transport assays were determined as described in Materials and Methods. The curve fitting to a hyperbolic equation was carried out using KaleidaGraph software with r > 0.99. Values are the mean ± SD (n = 3). Ins, Insulin; Tgz, troglitazone.

 
Troglitazone and insulin stimulate the same type of system A transport
To characterize the type of amino acid transport system that is stimulated by troglitazone, the substrate specificity and the initial uptake rate kinetics of MeAIB uptake were determined. The uptake of labeled 50 µM MeAIB in cells exposed to troglitazone or insulin was measured in the presence of a 10-mM concentration of various unlabeled amino acids. As shown in Fig. 4Go, the patterns of inhibition of both troglitazone- and insulin-stimulated MeAIB uptake were essentially identical and were characteristic of system A (31). Alanine, serine, proline, cysteine, and histidine inhibited the stimulated MeAIB uptake by more than 90%, and leucine, phenylalanine and threonine inhibited uptake by 60–80%. The cationic amino acids, lysine and arginine, were ineffective. An Eadie-Hofstee plot of the initial uptake rate kinetics after concomitant treatment with troglitazone and insulin yielded only a single component (Fig. 5Go), with a Km value (150 µM) close to that of 190 µM for the insulin-stimulated MeAIB transport in well differentiated adipocytes (30). The similarities in the pattern of differentiation dependence, substrate specificity, and transport kinetics suggest that troglitazone and insulin may stimulate the same type of system A transport in 3T3-L1 adipocytes. Moreover, as with insulin, troglitazone-stimulated MeAIB uptake was substantially attenuated by addition of cycloheximide and actinomycin D (>80% inhibition), indicating that troglitazone-stimulated amino acid transport also required de novo synthesis of the messenger RNA (mRNA) and proteins essential for system A function. This finding is consistent with transcriptional regulation of system A activity by insulin and other factors (1).



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  		Figure 4. Properties of the troglitazone-stimulated MeAIB uptake in 3T3-L1 cells. A, Inhibition of the troglitazone- and insulin-stimulated MeAIB uptake by selected amino acids, cycloheximide, and actinomycin D. On day 5 after the induction of differentiation the adipocytes were pretreated with 5 µM troglitazone or 100 nM insulin for 24 h. Transport of 50 µM MeAIB was determined in the presence or absence of 10 mM of selected amino acids. The transport assays were carried out as described in Materials and Methods. The troglitazone- and insulin-stimulated transport velocities were calculated by subtracting the uptake rates in unstimulated cells from those in stimulated cells. To inhibit transcription and translation, 1 µg/ml cycloheximide or actinomycin D was added 1 h before the addition of stimuli. Results were expressed as a percentage of the saturable uptake rate in control cells. The saturable uptake rates were calculated by subtracting the MeAIB uptake rates in the presence of 10 mM excess unlabeled MeAIB from the total uptake rates. Values are the mean ± SD (n = 3). AcD, Actinomycin D; ala, alanine; asp, aspartate; arg, arginine; BCH, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid; CHX, cycloheximide; cys, cysteine; glu, glutamate; his, histidine; leu, leucine; lys, lysine; phe, phenylalanine; pro, proline; ser, serine; trp, tryptophan.

 


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  		Figure 5. An Eadie-Hofstee plot of MeAIB uptake stimulated by 5 µM troglitazone and 100 nM insulin. After 2-day incubation with differentiation medium, the 3T3-L1 cells were incubated in serum-free DMEM medium containing 5 µM troglitazone and 100 nM insulin for 23 h and then switched to PBS.GMC with the stimuli. The stimulated MeAIB uptake velocities under each concentration of MeAIB were calculated by subtracting the uptake rate in unstimulated cells from that in stimulated cells. The linear least squares fit was carried out by using KaleidaGraph software with r > 0.99

 
We have demonstrated that the insulin-stimulated system A activity is less stable in 3T3-L1 cells during differentiation, and that a second insulin challenge required de novo synthesis of mRNA and proteins (30). Thus, it is possible that the synergistic effect of troglitazone is mediated by a decrease in the decay rate of the insulin-induced transport. To test this possibility, the stability of system A activity was measured after pretreating cells with insulin, troglitazone, or both. The rates of decay were unaffected by the presence of troglitazone (Fig. 6AGo). The sensitivity to cycloheximide and actinomycin D of the transport activity restimulated by insulin was then examined. Figure 6BGo shows that pretreating cells with troglitazone markedly enhanced the second stimulation by insulin. Although cycloheximide resulted in inhibition of the reinduced transport similar to that of previously induced transport (75%), actinomycin D was less effective in cells pretreated with troglitazone (60 vs. 90%; Fig. 6CGo), suggesting that troglitazone may potentiate the response to insulin by stabilization of mRNA important for system A activity. These results are similar to the previous observations of glucose transport in 3T3-F442A cells, in which pioglitazone, another TZD compound, was suggested to increase GLUT1 and GLUT4 transport by mRNA stabilization (17).



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  		Figure 6. Effect of troglitazone pretreatment on the decay and reinduced MeAIB uptake by insulin in 3T3-L1 cells. A, Decay of the stimulated MeAIB uptake by insulin and/or troglitazone. The 3T3-L1 cells on day 2 after the induction of differentiation were pretreated with 100 nM insulin and/or 5 µM troglitazone for 24 h. After sufficient washing with PBC.GMC, decay of the previously stimulated MeAIB uptake was determined over the 8-h time course. Regression analysis was carried using KaleidaGraph software to fit curves to the equation: y = a x e-bx (r > 0.99) in which y is the percentage of MeAIB uptake rates compared with that at zero time, and x is the time after removing stimuli (hours). B, Time course of reinduced MeAIB uptake by insulin. The cells (day 2) were pretreated with a combination of 5 µM troglitazone and 100 nM insulin for 24 h and then incubated in PBC.GMC for 4 h as described above. The restimulated MeAIB uptake by a second insulin treatment was determined at the times indicated. C, Inhibition of the restimulated MeAIB uptake by cycloheximide and actinomycin D. Cycloheximide and actinomycin D (1 µg/ml) were added to the same cells as those in A 1 h before a second stimulation by insulin. B* to B to I was incubation in serum-free DMEM for 24 h, then in PBS.GMC for 4 h, then in insulin-containing PBS.GMC for 5 h; I to B to I was the same as described above, except for the pretreatment in insulin-containing DMEM for 24 h; and I+T to B to I was pretreated in DMEM containing troglitazone and insulin. Transport assays were carried out as described in Materials and Methods. Values are the mean ± SD (n = 3). AcD, Actinomycin D; CHX, cycloheximide; Ins, insulin; Tgz, troglitazone.

 
MeAIB uptake is also stimulated by other compounds of TZD class
Glucose transport can be induced by a variety of TZDs, including troglitazone (16, 18, 20, 21, 32), pioglitazone (17, 19, 32), and BRL49653 (22). To test whether the stimulation of MeAIB uptake by troglitazone is also common to the class of TZD, the effects of BRL49653 were compared. As with troglitazone, BRL49653 exhibited both insulinomimetic and insulin-enhancing effects on MeAIB uptake (Fig. 7Go). Moreover, similar effects were observed with pioglitazone and ciglitazone (data not shown). In contrast to the effect on insulin, however, coadministration of troglitazone and BRL49653 appeared not to further increase the uptake velocities induced by either agent alone, suggesting that this class of drugs activates system A transport though the same mechanism.



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  		Figure 7. Stimulation of MeAIB uptake by combination of troglitazone, BRL49653, and insulin. The adipocytes on day 4 after the induction of differentiation were incubated in serum-free DMEM containing the corresponding drugs (5 µM) with or without 100 nM insulin. One hour before the transport assays, the cells were switched to PBS.GMC with the agents to be tested. Transport assays were carried out as described in Materials and Methods. Values are the mean ± SD (n = 3). CTRL, Unstimulated control cells; BRL, BRL49653; Ins, insulin; Tgz, troglitazone.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Although it is well established that TZDs are potent insulin sensitizers, the precise sequellae of molecular changes in insulin action have been difficult to elucidate in animal models of insulin resistance due mainly to the complex feedback systems typical of the regulation of metabolism (3). Such homeostatic loops are generally not present in tissue culture cell lines, offering an opportunity to study the biochemical events important to the actions of these drugs. One especially useful line is the 3T3-L1 cell, which can be induced to differentiate into highly insulin-responsive adipocytes. We demonstrate here that TZDs, such as troglitazone, increase system A amino acid transport in 3T3-L1 cells by an insulin-independent as well as an insulin-dependent mechanism.

Kinetic characterization of amino acid transport in insulin- and troglitazone-treated 3T3-L1 cells indicates that system A is similarly responsive to both agents. Moreover, the effects of troglitazone take several hours and are most evident in newly differentiated adipocytes. These effects, which are characteristic of those of insulin, strongly suggest a transcriptional mechanism for both agents, probably involving increased expression of an unknown gene(s) encoding components of system A transport. The dose response for this effect of troglitazone and the similar increases observed with other TZDs suggest that this effect is mediated by activation of PPAR{gamma}, although it is not possible to determine whether the putative increase in transcription is a direct or an indirect consequence of PPAR{gamma} activation. Interestingly, this is one of the few effects of TZDs that have been demonstrated in terminally differentiated adipocytes, suggesting that this may reflect an important physiological effect of these agents on metabolism that is unrelated to enhanced differentiation of adipocytes.

In addition to its insulin-mimetic effect on system A transport, troglitazone increased the sensitivity of cells to insulin. As mentioned above, the stimulatory effect of insulin on system A is presumed to be primarily transcriptional. Troglitazone markedly enhanced the sensitivity of this effect of insulin, with a 4- to 5-fold shift in the dose-response curve. Interestingly, this effect was most clearly observed during the early stages of differentiation. The mechanism of the insulin-sensitizing effect is not known. It may reflect improved signaling for insulin (22) or reductions in attenuation of insulin action by autocrine cytokines such as tumor necrosis factor (18). Alternatively, it is possible that the improvement in insulin sensitivity may require expression of other factors, perhaps including those involved in preserving mRNA stability.

The regulation of amino acid and protein metabolism is defective in states of diabetes and insulin resistance. Because system A is likely to represent the major insulin-sensitive pathway for amino acid transport, its regulation is likely to play a large part in influencing hormonally regulated protein synthesis. The results presented here suggest that one aspect of the action of troglitazone and other TZDs may be to up-regulate the expression of genes encoding for components of this transport system. The identification of these genes and elucidation of the mechanisms by which they are regulated may help to further our understanding of the molecular defects underlying insulin resistance.

Received August 25, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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