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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 7 3130-3133
Copyright © 2001 by The Endocrine Society

Original Articles

Troglitazone Reduces the Expression of PPAR{gamma} While Stimulating That of PPAR{alpha} in Mononuclear Cells in Obese Subjects1

Ahmad Aljada, Husam Ghanim, Jay Friedman, Rajesh Garg, Priya Mohanty and Paresh Dandona

Division of Endocrinology, Diabetes, and Metabolism, State University of New York at Buffalo and Kaleida Health, Buffalo, New York 14209

Address all correspondence and requests for reprints to: Paresh Dandona, M.D., Ph.D., Diabetes-Endocrinology Center of WNY, 3 Gates Circle, Buffalo, New York 14209. E-mail: pdandona{at}kaleidahealth.org

Abstract

We have recently demonstrated that troglitazone exerts an anti-inflammatory effect in the insulin resistant obese in vivo in parallel with its insulin-sensitizing effect. Because these effects are thought to be mediated through peroxisome proliferator-activated receptors {alpha} and {gamma} (PPAR{alpha} and PPAR{gamma}), we have now examined the possibility that troglitazone may modulate the expression of PPAR{alpha} and PPAR{gamma}. Seven obese hyperinsulinemic subjects were administered 400 mg troglitazone daily for 4 weeks. Fasting blood samples were obtained before and during troglitazone therapy at 1, 2, and 4 weeks. Fasting insulin concentrations fell at week 1 and persisted at lower levels till 4 weeks. PPAR{gamma} expression fell significantly at week 1 and fell further at weeks 2 and 4. In contrast, PPAR{alpha} expression increased significantly at week 2 and further at week 4. 9- and 13-hydroxyoctadecanoic acid, products of linoleic acid peroxidation and agonists of PPAR{gamma}, decreased during troglitazone therapy. We conclude that troglitazone, an agonist for both PPAR{alpha} and PPAR{gamma}, has significant but dramatically opposite effects on PPAR{alpha} and PPAR{gamma}. These effects may be relevant to its insulin sensitizing and anti-inflammatory effects.

TROGLITAZONE IS A thiazolidinedione, a class of drugs known to increase sensitivity to the action of insulin. Thiazolidinediones are thus used in type 2 diabetes to reduce insulin resistance and to lower blood glucose concentrations (1, 2). We have recently demonstrated an antioxidant effect of troglitazone with a reduction in reactive oxygen species (ROS) generation by leukocytes and a reduction in lipid peroxidation in vivo (3).

More recently, we have also demonstrated that troglitazone may have a potent anti-inflammatory action with a suppressive action on nuclear factor {kappa}B (NF{kappa}B) in mononuclear cells (MNC) and a stimulatory action on I{kappa}B, the inhibitor of NF{kappa} B (4). These changes in anti-inflammatory effects are observed within 7 days of starting troglitazone and parallel similar falls in fasting insulin concentrations. This suggests that both insulin sensitization and anti-inflammatory effects of troglitazone probably mediated by peroxisome proliferator-activated receptors {alpha} and {gamma} (PPAR{gamma} and PPAR{alpha}) are rapid and occur in parallel (5, 6). We have therefore now examined the possibility that PPAR{alpha} and PPAR{gamma} may be modulated by troglitazone in MNC. This communication describes the sequential effect of troglitazone on PPAR{gamma} and PPAR{alpha} in MNC. Plasma concentrations of 9- and 13-hydroxyoctadecanoic acid (9-HODE and 13-HODE) were also measured because these oxidatively damaged products of linoleic acid are now known to be agonists of PPAR{gamma} (7).

Subjects, Materials, and Methods

Subjects

Seven obese subjects (age range 32–52 yr, mean 40.6 ± 8.0 yr), all with body mass index (BMI) greater than 37 kg/m2, (BMI range 37.0–60.9, mean: 46.1 ± 8.7 kg/m2) were included in this study (Table 1Go). None of the obese subjects was on vitamin E or C or any other antioxidant therapy. The subjects were not advised any special diet, and none of them was actively trying to lose weight during the period of the study. The Institutional Review Board approved the study. Written informed consent was obtained from all subjects.


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  		Table 1. Demographic data on the obese patients included in the study

 
Baseline liver function tests were carried out in each patient. The patients were given 400 mg troglitazone daily for 4 weeks. A weekly follow-up was done to note any side effects of the drug and to collect fasting blood samples in Na-EDTA at each weekly visit. A tablet count was carried out every week to verify the compliance. Liver function tests were repeated at the end of 4 weeks.

MNC isolation

Three and a half milliliters of the anticoagulated blood sample were carefully layered over 3.5 mL of PMN medium (Robbins Scientific Corp., Sunnyvale, CA). The sample was centrifuged at 450 x g for 30 min at 22 C. At the end of the centrifugation, two bands separate out at the top of the red blood cell pellet. The top band consists of MNC, and the bottom consists of PMN. The bands were harvested, repeatedly washed with HBSS, and reconstituted to a concentration of 4 x 105 cells/mL in HBSS. This method provides yields greater than 95% pure PMN and MNC suspensions. This was tested repeatedly to validate this method. Thereafter, random checks were made to ensure the purity of the preparations.

13-HODE and 9-HODE measurements

Hydroxy polyunsaturated fatty acids were measured by a modification of the high-performance liquid chromatography based method as previously described (3).

PPAR{alpha} and PPAR{gamma} Western blotting

MNC cell lysates were prepared by adding 1 mL boiling lysis buffer (1% SDS, 1 mM sodium ortho-vanadate, 10 mM Tris, pH 7.4) to the MNC pellets. Total protein concentrations were determined using BCA protein assay (Pierce Chemical Co., Rockland, IL). Sixty micrograms of total cell lysate were electrophoresed on 8% SDS polyacrylamide gels. The proteins were transferred to polyvinylidene difluoride membrane, blocked for 1 h in 5% nonfat dry milk, and then incubated for 1 h with polyclonal antibodies against PPAR{alpha} or PPAR{gamma} (Affinity BioReagents, Inc., Golden, CO). Finally, the membrane was washed and developed using super signal, chemiluminescence reagent (Pierce Chemical Co.). Densitometry was performed using Bio-Rad Laboratories, Inc. molecular analyst software (Hercules, CA). These measurements were carried out at 0, 1, 2, and 4 weeks.

Plasma immunoreactive insulin, glucose

Insulin was measured from fasting plasma samples using an enzyme-linked immunosorbent assay kit (Diagnostics Systems Laboratories, Inc., Webster, TX). Glucose was measured by Hexokinase method.

Statistical analysis

Statistical analysis was performed using SigmaStat software (Jandel Scientific, San Rafael, CA). Kruskal-Wallis one-way ANOVA on ranks was used to compare the indices measured in this study.

Results

Plasma glucose, immunoreactive insulin, and lipid concentrations

Plasma glucose concentrations did not alter significantly following troglitazone (week 0: 5.28 ± 0.83 mmol/L; week 1: 5.17 ± 0.49 mmol/L; week 2: 5.20 ± 0.59 mmol/L; and week 4: 5.13 ± 0.62 mmol/L). Plasma insulin concentrations fell significantly at week 1 and fell further by week 4. Plasma insulin concentrations fell from 31.2 ± 26.9 µU/mL at baseline to 14.2 ± 10.5 µU/mL at week 1, 6.9 ± 2.8 µU/mL at week 2 and 7.3 ± 4.9 µU/mL at week 4. Serum lipids, including total cholesterol and triglycerides, did not alter significantly.

Plasma 9-HODE and 13-HODE concentrations

Plasma 9-HODE concentrations fell from 787.4 ± 52.4 to 754.8 ± 48.5 at week 2 and 720.36 ± 66.7 nmol/L at 4 weeks (P < 0.05). Plasma 13-HODE concentrations fell from 713.1 ± 44.7 to 692.1 ± 67.0 at week 2 and 675.2 ± 65.0 nmol/L at week 4 (P < 0.05).

PPAR{gamma} and PPAR{alpha} expression

PPAR{gamma} protein content fell markedly from a basal level of 100% to 70 ± 5.4% at week 1, 21 ± 4.4% at week 2 and 38 ± 14.9% at week 4. This decrease was significant at 1, 2, and 4 weeks following troglitazone intake (P < 0.05; Fig. 1Go). PPAR{alpha} protein content increased significantly at week 1 and continued to increase until week 4. It increased from a basal level of 100% to 148 ± 28% at week 1, 306 ± 108% at week 2 and 437 ± 167% at week 4 (P < 0.05; Fig. 2Go).



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  		Figure 1. A, A representative Western blot showing the relative expression of PPAR{gamma} in MNC following troglitazone intake. B, Densitometric quantitative analysis of PPAR{gamma} protein contents in MNC. The results are presented as mean ± SE (*, P < 0.05).

 


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  		Figure 2. A, A representative Western blot showing the relative expression of PPAR{alpha} in MNC following troglitazone intake. B, Densitometric quantitative analysis of PPAR{alpha} protein contents in MNC. The results are presented as mean ± SE (*, P < 0.05).

 
Discussion

Our data demonstrate for the first time that PPAR{gamma} is expressed abundantly in MNC in the obese and that its expression falls rapidly within 1 week following treatment with a modest dose (400 mg) of troglitazone, in parallel with a fall in insulin. The fall persisted throughout 4 weeks of troglitazone administration. This change was observed in each of the seven subjects. Because glucose and lipid concentrations did not alter, this effect was independent of plasma glucose, cholesterol, and triglycerides. Whether PPAR{gamma} expression is a function of insulin resistance and whether it falls in parallel with processes governing insulin resistance like NF{kappa}B will require further investigation. Our data also show that PPAR{alpha} expression increases within 1 week of troglitazone, which is also known to be a PPAR{alpha} agonist. Whether this effect is directly attributable to troglitazone action or is mediated by a fall in insulin resistance and insulin concentrations or by other events like NF{kappa}B inhibition is not clear. It is known that PPAR{alpha} may have an anti-inflammatory role (5), and, thus, NF{kappa}B- or NF{kappa}B-mediated effects may modulate both the expression of PPAR{alpha} and the effects of PPAR{gamma}. 9-HODE and 13-HODE are also known to be ligands of PPAR{gamma} (7), and their decrease following troglitazone administration may contribute to alterations in PPAR{gamma} expression. Indeed, 9-HODE and 13-HODE are constituents of oxidized low-density lipoprotein (ox-LDL), which modulates both the expression of PPAR{gamma} in the monocyte and the formation of foam cells (7, 8). Previous work shows that troglitazone prevents the decrease in the expression of PPAR{gamma} induced by proinflammatory cytokines in mature rat adipocytes. This effect was not observed in the absence of the inhibitory effect of proinflammatory cytokines like tumor necrosis factor {alpha} (TNF{alpha}) (9). It is of interest that in human MNC in vivo, the fall in PPAR{gamma} expression occurs in association with a fall in TNF{alpha} induced by troglitazone (4). The diametrically opposite effect of troglitazone on PPAR{gamma} expression in the rat adipocytes in vitro, when compared with that on human MNC in vivo, could either be due to the difference in the behavior of the two cell types or a species difference. It could also be due to the concentrations of troglitazone used. Our data are naturally more relevant to human pathophysiology because our experiments were carried out in humans in vivo using modest therapeutic doses of troglitazone.

Although there are hitherto no data on the modulation of PPAR{alpha} and PPAR{gamma} expression in the human in vivo, PPAR{gamma}1 and PPAR{gamma}2 expression in adipocytes in some models of obesity has been shown to be increased. On the other hand, a fast causes a rapid fall in PPAR{gamma} expression in adipocytes by as much as 60–80% over a period of 48 h (10).

It has been claimed that human monocytes do not express PPAR{gamma} (11), but macrophages in atherosclerotic lesions express PPAR{gamma} (12). In our studies, we have used mononuclear cell populations, which contain a mix of monocytes and lymphocytes. We tested this population because all of our previous work on ROS generation and the anti-inflammatory effects of glucocorticoids (13), ß-blockers carvedilol and nadolol (14, 15), and troglitazone (3, 4) has used this cell population. Because it is known that oxidized LDL induces the expression of PPAR{gamma} (7), it is possible that increased lipid peroxidation and an increase in 9-HODE and 13-HODE concentrations in the obese previously described by us (3, 16), may contribute to the expression of PPAR{gamma} in the mononuclear cell population from the obese. Activation of PPAR{alpha} has been shown to inhibit the induced expression of endothelin-1 in endothelial cells, cyclooxygenase-2 and interleukin-6 in vascular smooth muscle cells, TNF{alpha} and interleukin-2 in monocytes, and class A scavenger receptor and inducible nitric oxide synthase in activated macrophages (17, 18, 19). These actions are achieved through interference with the action of the proinflammatory transcription factors, NF{kappa}B, and activator protein-1 (17, 19). We have recently demonstrated that serum TNF{alpha}, soluble intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and C-reactive protein are all diminished following treatment with troglitazone in the obese (4). These observations would be consistent with PPAR{alpha} and PPAR{gamma} mediated anti-inflammatory effects of troglitazone. This is probably also achieved through ox-LDL-induced increase in PPAR{gamma} expression in the monocyte/macrophage as well as simultaneous increase in the scavenger receptor CD36, which binds and internalizes ox-LDL and may lead to foam cell formation. Because class A scavenger receptor-mediated uptake of ox-LDL and the additional actions of activator protein-1 and NF{kappa}B (protection from apoptosis) also participate in the process of foam cell formation, there may be other roles for PPAR{gamma} and its agonists because thiazolidinediones have now been shown to be inhibitors of NF{kappa}B (4, 17).

To test the role of PPAR{gamma} in the pathogenesis of insulin resistance, Miles et al. (20) have investigated PPAR{gamma} knockout mice. Although the homozygous PPAR{gamma} -/- mouse is unable to survive (incompatible with life), the heterozygous PPAR{gamma} ± mouse is hypersensitive to insulin. Thus, PPAR{gamma} ± mice with 50% PPAR{gamma} have lower insulin concentrations following a glucose challenge than the wild-type +/+ mice. This suggests that PPAR{gamma} may exert an effect that increases insulin resistance. This is paradoxical because PPAR{gamma} with its ligand mediates sensitization to insulin. It is possible that although PPAR{gamma} with an appropriate ligand has a particular transcriptional activity, the receptor without a ligand binds to DNA without inducing transcription, thus blocking transcription. Our data appear consistent with this concept because in the insulin-resistant obese, PPAR{gamma} expression is high. Following treatment with troglitazone, PPAR{gamma} content falls in parallel with a fall in fasting insulin concentrations in plasma. It is thus possible that in the absence of a ligand, PPAR{gamma} increases to further increase insulin resistance.

In contrast to PPAR{gamma} suppression following troglitazone, the role of PPAR{alpha} enhancement following this drug has obvious clinical implications. PPAR{alpha} modulates the expression of fatty acid-binding protein and peroxisomal acyl-CoA oxidase (21). Acyl CoA-oxidase is an enzyme responsible for fatty acid oxidation (22), and thus an increase in PPAR{alpha} may enhance the metabolism of fatty acids and thus lower fatty acid concentration, which is believed to be cardinal to the action of troglitazone.

We conclude that troglitazone, a PPAR{alpha} and a PPAR{gamma} agonist, has profound and diametrically opposite effects on the expression of PPAR{gamma} (inhibitory) and PPAR{alpha} (stimulatory). This may have implications in the mediation of its anti-inflammatory effects and its effects on the restoration of insulin sensitivity in the obese. These effects may also have relevance to atherogenesis in the long term.

The study was completed 6 months before the withdrawal of troglitazone from the market. The subjects were informed about the potential hepatotoxicity of the drug while signing the contract. The Institutional Review Board was informed about the association of potential hepatotoxicity of the drug.

Acknowledgments

We gratefully acknowledge the support of McGowan Charitable Fund.

Footnotes

1 Supported by a grant from Parke-Davis (now Pfeifer). Back

Received October 30, 2000.

Revised February 27, 2001.

Accepted March 6, 2001.

References

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