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PubMed2005

Peroxisome proliferator-activated receptor gamma agonist troglitazone induces colon tumors in normal C57BL/6J mice and enhances colonic carcinogenesis in Apc1638 N/+ Mlh1+/- double mutant mice.

The role of the nuclear peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in colon tumorigenesis remains controversial. Notwithstanding evidence that PPAR-gamma ligands impede murine colorectal carcinogenesis, PPAR-gamma agonists have been shown to enhance in vivo tumor formation in mouse models of human colon cancer. Our study was designed to determine whether troglitazone (TGZ) induces colonic tumor formation in normal C57BL/6J mice and enhances colorectal carcinogenesis in double mutant Apc1638N/+ Mlh1+/- mice fed a standard AIN-76A diet. We report herein that not only does TGZ enhance carcinogenesis in the large intestine of mutant mice predisposed to intestinal carcinogenesis but TGZ also induces colonic tumors in normal mice without gene targeting or carcinogen administration. This observation indicates that preexisting mutational events are not necessary for induction of colonic tumors by activated PPAR-gamma in vivo.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Activation of peroxisome proliferator-activated receptor-gamma by troglitazone (TGZ) inhibits human lung cell growth.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors and a crucial regulator of cellular differentiation. PPAR-gamma ligands have been demonstrated to inhibit growth of several cancer cells. In this study, two human lung cancer cells (NCI-H23 and CRL-2066) and one human lung normal cell (CRL-202) were used for the experiments. The results showed that in consistence with the loss of viability, troglitazone (TGZ) induced apoptosis of CRL-2066 and NCI-H23 cells but not CCL-202 cells. TGZ upregulated PPAR-gamma expression in all the three lung cell lines, especially in the cancer cells. In association of the time-dependent inhibition of the cell proliferation, TGZ downregulated the expression of Bcl-w and Bcl-2 but activated extracellular signal-regulated kinase (ERK)1/2 and p38, suggesting that the growth-inhibitory effect of TGZ is associated with the reduction of Bcl-w and Bcl-2 and the increase of ERK1/2 and p38 activation. SAPK/JNK activation assay showed a decreased activity in all the three cell lines tested after TGZ treatment. It was also demonstrated that TGZ could activate PPAR-gamma transcriptionally. We conclude that TGZ inhibits growth of human lung cancer cells via the induction of apoptosis and the inhibition of cell growth, at least in part, in a PPAR-gamma-relevant manner. The mechanism of TGZ is associated with the activation of ERK and p38, the reduction of SAPK/JNK activity, and the alteration of Bcl-w and Bcl-2.

Apoptosis↗
PubMed2006

Apoptosis induced by troglitazone is both peroxisome proliferator-activated receptor-gamma- and ERK-dependent in human non-small lung cancer cells.

The role of the peroxisome proliferator-activated receptor-gamma (PPARgamma) in cell differentiation, cell-cycle arrest, and apoptosis has attracted increasing attention. We have recently demonstrated that PPARgamma ligands-troglitazone (TGZ) induced apoptosis in lung cancer cells. In this report, we further studied the role of ERK1/2 in lung cancer cells treated by TGZ. The result demonstrated that TGZ induced PPARgamma and ERK1/2 accumulation in the nucleus, in which the co-localization of both proteins was found. The activation of ERK1/2 resulted in apoptosis via a mitochondrial pathway. Both PPARgamma siRNA and U0126, a specific inhibitor of ERK1/2, were able to block these effects of TGZ, suggesting that apoptosis induced by TGZ was PPARgamma and ERK1/2 dependent. Inhibition of ERK1/2 by U0126 also led to a significant decrease in the level of PPARgamma, indicating a positive cross-talk between PPARgamma and ERK1/2 or an auto-regulatory feedback mechanism to amplify the effect of ERK1/2 on cell growth arrest and apoptosis. In addition to ERK1/2, TGZ also activated Akt. Interestingly, inhibition of ERK1/2 prevented the activation of Akt whereas the suppression of Akt had no effect on ERK1/2, suggesting that Akt was not necessary for TGZ-PPARgamma-ERK pathway. However, the inhibition of Akt promoted the release of cytochrome c, suggesting the activation of Akt may have a negative effect on apoptosis induced by TGZ. In conclusion, our study has demonstrated that TGZ, a synthetic PPARgamma ligand, induced apoptosis in NCI-H23 lung cancer cells via a mitochondrial pathway and this pathway was PPARgamma and ERK1/2 dependent.

Apoptosis↗
PubMed2000

Insulin sensitizer, troglitazone, directly inhibits aromatase activity in human ovarian granulosa cells.

Ovarian granulosa cells synthesize estrogens from androgens, which are catalyzed by aromatase cytochrome P450 (P450arom). Troglitazone (Tro), one of the insulin-sensitizing compounds, thiazolidinediones (TZDs), is a ligand for peroxisome proliferator activated receptor gamma (PPARgamma) and is effective in the treatment of both non-insulin-dependent diabetes mellitus (NIDDM) as well as polycystic ovary syndrome (PCOS). PPARgamma exerts a transcriptional activity as a PPARgamma:RXR heterodimer. In this study, we investigated the effects of Tro and/or RXR ligand, LG100268 (LG) on the aromatase activity in cultured human ovarian granulosa cells obtained from patients who underwent in vitro fertilization. Human ovarian granulosa cells expressed PPARgamma mRNA assessed by RT-PCR. The treatment of the granulosa cells with Tro for 24 h resulted in a dramatic inhibition of the aromatase activity in a dose-dependent manner. While the treatment with LG alone also inhibited the aromatase activity, the combined treatment with both Tro and LG caused a much more reduction in the aromatase activity. The changes in the aromatase activity by Tro and/or LG were associated with comparable changes in P450arom mRNA assessed by RT-PCR. These results suggest that Tro directly inhibit the aromatase activity in human granulosa cells probably via nuclear receptor system PPARgamma:RXR heterodimer. The findings may provide a biochemical basis for the decrease in the blood concentrations of estrogens which is observed after the in vivo administration of Tro and may also possibly be useful as a novel therapy for estrogen-dependent diseases.

Adult↗
PubMed2001

Effects of troglitazone on cellular differentiation, insulin signaling, and glucose metabolism in cultured human skeletal muscle cells.

To determine the immediate effect of thiazolidinediones on human skeletal muscle, differentiated human myotubes were acutely (1 day) and myoblasts chronically (during the differentiation process) treated with troglitazone (TGZ). Chronic TGZ treatment resulted in loss of the typical multinucleated phenotype. The increase of muscle markers typically observed during differentiation was suppressed, while adipocyte markers increased markedly. Chronic TGZ treatment increased insulin-stimulated phosphatidylinositol (PI) 3-kinase activity and membranous protein kinase B/Akt (PKB/Akt) Ser-473 phosphorylation more than 4-fold. Phosphorylation of p42/44 mitogen-activated protein kinase (42/44 MAPK/ERK) was unaltered. Basal glucose uptake as well as both basal and insulin-stimulated glycogen synthesis increased approximately 1.6- and approximately 2.5-fold after chronic TGZ treatment, respectively. A 2-fold stimulation of PI 3-kinase but no other significant TGZ effect was found after acute TGZ treatment. In conclusion, chronic TGZ treatment inhibited myogenic differentiation of that human muscle while inducing adipocyte-specific gene expression. The effects of chronic TGZ treatment on basal glucose transport may in part be secondary to this transdifferentiation. The enhancing effect on PI 3-kinase and PKB/Akt involved in both differentiation and glycogen synthesis appears to be pivotal in the cellular action of TGZ.

Adipocytes↗
PubMed2001

Troglitazone inhibits growth of MCF-7 breast carcinoma cells by targeting G1 cell cycle regulators.

Peroxisome proliferator activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily. Ligand activation of PPARgamma has been shown to cause growth arrest in several human tumor cell types, but the underlying molecular mechanism has not been elucidated. We report here that the PPARgamma ligand troglitazone (TRO) inhibited MCF-7 cell proliferation by blocking events critical for G1 --> S progression. Flow cytometry demonstrated that TRO at 20 microM increased the percentage of cells in G1 from 51 to 69% after 24 h. Accumulation of cells in G1 was accompanied by an attenuation of Rb protein phosphorylation associated with decreased CDK4 and CDK2 activities. Inhibition of CDK activity by TRO correlates with decreased protein levels for several G1 regulators of Rb phosphorylation (cyclin D1, and CDKs 2, 4, and 6). Overexpression of cyclin D1 partially rescued MCF-7 cells from TRO-mediated G1 arrest. Targeting of G1 regulatory proteins, particularly cyclin D1, and the resulting induction of G1 arrest by TRO may provide a novel antiproliferative therapy for human breast cancer.

Annexin A5↗
PubMed2000

Troglitazone and emerging glitazones: new avenues for potential therapeutic benefits beyond glycemic control.

Insulin resistance is characterized as one of the major pathogeneses of type 2 diabetes and has been associated with these same cardiovascular risk factors. Troglitazone, rosiglitazone, and pioglitazone are a new class of oral antidiabetic agents which can ameliorate peripheral insulin resistance in type 2 diabetes. There is considerable evidence that trogliterazone may have beneficial effects on cardiovascular and metabolic abnormalities associated with insulin resistance. There is supportive evidence for positive effects of the other glitazones, but they have been less well studied. These potential benefits span effects ranging from molecular events in the arterial wall to amelioration and/or improvement in lipid parameters known to be associated with atherosclerosis.

Animals↗
PubMed2001

Troglitazone and rosiglitazone induce apoptosis of vascular smooth muscle cells through an extracellular signal-regulated kinase-independent pathway.

Recent evidence suggests that apoptosis may be involved in the control of vascular smooth muscle cell (VSMC) number in atherosclerotic lesions. The peroxisome proliferator-activated receptor gamma (PPARgamma) ligands thiazolidinediones have been reported to induce apoptosis in macrophages and in a variety of tumor cell lines. To evaluate whether these agents also induce apoptosis in VSMC, cultured rat VSMC were treated with increasing doses of the thiazolidinedione analogues troglitazone (TRO) and rosiglitazone (RSG). Both ligands induced cell death in a concentration-dependent manner (EC50 12.1+/-3.3 microM and 1.43+/-0.39 microM, respectively), causing almost complete cell death at the highest concentrations (100 microM and 10 microM for TRO and RSG, respectively), along with an expected parallel decrease in [3H]thymidine uptake into cell DNA (EC50 6.7+/-2.4 microM and 0.75+/-0.19 microM, respectively). The cell count was determined by the coulter counter principle. Furthermore two apoptotic markers were measured, the caspase 3 activity and the cytoplasmic histone-associated DNA fragments, both of which were significantly increased when the aforementioned high concentrations were used. This indicates that apoptosis is involved in the TRO- and RSG-induced VSMC growth suppression. The same concentrations of TRO and RSG caused an unexpected stimulation of the extracellular signal-regulated response kinases 1 and 2 (ERK1/2) and stimulated the p38 mitogenic-activated protein (MAP) kinase as determined by Western blotting. In order to establish whether the proapoptotic effects of TRO and RSG are mediated through ERK1/2 activation, we used the selective MAP kinase kinase (MEK) inhibitor PD98059 (20 microM), which suppressed the TRO- and RSG-induced ERK1/2 activation but did not abolish their proapoptotic effects. We conclude that the thiazolidinedione analogues TRO and RSG induce cell death due to apoptosis in VSMC through an ERK1/2-independent pathway.

Animals↗
PubMed2003

Induction of differentiation and peroxisome proliferator-activated receptor gamma expression in colon cancer cell lines by troglitazone.

PURPOSE: We investigated the relationship between the effects of troglitazone (TGZ) on cellular growth, differentiation and apoptosis induction, and the induction of peroxisome proliferator-activated receptor (PPAR) gamma in three human colon cancer cell lines, HCT-15, DLD-1and LoVo. METHODS: Viable cell number was evaluated by the Alamar blue assay and apoptotic cell death by TUNEL methods. Expression of PPARgamma mRNA and protein was examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, respectively. The differentiation markers of colonic mucosa, villin and MUC2 mRNAs, were analyzed by real-time RT-PCR. RESULTS: HCT-15 and DLD-1 cells proliferated rapidly while LoVo cells grew slowly. TGZ dose-dependently inhibited the proliferation of all the cell lines, and also induced apoptotic cell death. High expression of PPARgamma mRNA and protein was demonstrated in DLD-1 and LoVo cells before TGZ treatment. After the treatment, PPARgamma mRNA and protein levels were increased in HCT-15 and LoVo cells. Villin and MUC2 mRNAs were increased by TGZ treatment in HCT-15 cells while villin mRNA was repressed in LoVo cells. Changes in expression of PPARgamma, villin or MUC2 mRNAs were not observed in DLD-1 cells. CONCLUSIONS: These results suggest that PPARgamma levels are not correlated with the rates of cell proliferation. Differentiation induction by TGZ was only observed in the cell lines with enhanced PPARgamma expression.

Apoptosis↗
PubMed2000

Effects of fructose and troglitazone on phospholipid fatty acid composition in rat skeletal muscle.

Skeletal muscle phospholipid fatty acid (PLFA) composition is associated with insulin sensitivity in animal models and in man. However, it is not clear whether changes in insulin sensitivity cause a change in PLFA composition or vice versa. The present studies have examined the effects of agents known to increase or decrease insulin sensitivity on PLFA composition of the major phospholipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), in soleus and extensor digitorum longus muscle. Four groups of Sprague-Dawley rats--control, 0.2% troglitazone (Tgz), 60% fructose fed, and fructose + Tgz--were treated for 3 wk. Fructose feeding was associated with a decrease in muscle membrane polyunsaturated fatty acids (PUFA) and n-3 fatty acids in both PC and PE. Administration of Tgz alone resulted in an increase in liver (3.75 +/- 0.93 to 6.93 +/- 1.00 micromol/min/mg tissue, P < 0.05) and soleus muscle (0.34 +/- 0.03 to 0.67 +/- 0.09 micromol/min/mg, P < 0.01) elongase activity, which would be expected to increase membrane PUFA. However, Tgz decreased PLFA associated with greater insulin sensitivity (e.g., PUFA and n-3 fatty acids) and increased PLFA associated with decreased insulin sensitivity (16:0 and n-6 fatty acids) in both PC and PE. Co-administration of fructose and Tgz did not reverse the decrease in PUFA observed with fructose alone. We conclude that the improvement in insulin sensitivity reported with Tgz is associated with an apparently paradoxical effect to decrease PUFA and n-3 PLFA composition in rat skeletal muscle. These studies suggest that Tgz-mediated increases in insulin sensitivity do not result in improved PLFA composition.

Animals↗
PubMed2006

Effects of conjugated linoleic acid and troglitazone on lipid accumulation and composition in lean and Zucker diabetic fatty (fa/fa) rats.

Dietary CLA has been shown to enhance glucose tolerance in several animal models, but in mice it induces insulin resistance and lipodystrophy. In this study, the effects of 2 wk of diet supplementation with either 1.5% CLA or 0.2% troglitazone (TZD), an insulin-sensitizing thiazolidinedione, on glucose tolerance, lipid accumulation, and composition of both lean and Zucker diabetic fatty (fa/fa; ZDF) rats were examined. Compared with lean rats, which maintained normal glucose tolerances after 2 wk of feeding regardless of diet, ZDF rats fed a control diet (CON) had significantly worsened glucose tolerance. ZDF rats fed CLA and TZD diets, however, maintained normal glucose tolerances. In contrast to the significantly elevated lipid levels in ZDF rats fed the CON diet, concentrations of plasma FFA and TG in ZDF rats fed CLA and TZD diets were normalized. A similar reduction of plasma lipid levels was observed in lean rats fed CLA and TZD compared with lean rats fed the CON diet. Although ZDF CON rats developed significant hepatic steatosis, both CLA- and TZD-fed rats had hepatic TG levels similar to those of lean rats. Both lean and ZDF rats fed the CLA diet had reduced adipose mass compared with respective genotype controls; however, TZD had no effect. Ratios of 16:1/16:0 and 18:1/18:0 FA, surrogate markers for stearoyl-CoA desaturase-1 (SCD-1) activity, were reduced in livers of ZDF rats fed CLA and TZD diets. These results show that, like TZD, CLA normalizes glucose tolerance and plasma lipids and also improves hepatic steatosis and FA composition in ZDF rats. The effects of CLA and TZD on hepatic lipid composition suggest that the effects of these two agents on glucose tolerance may be associated with a reduction in SCD-1.

Adipose Tissue↗
PubMed1995

High-performance frontal analysis for the study of protein binding of troglitazone (CS-045) in albumin solution and in human plasma.

An on-line frontal analysis HPLC system was developed for the determination of the unbound concentration of troglitazone (CS-045), a new oral antidiabetic agent, in human serum albumin (HSA) solution and in human plasma. This system consists of a high-performance frontal analysis (HPFA) column, an extraction column, and an analytical column, which are connected via two switching valves. After the direct injection of the sample solution into the HPFA column, the drug was eluted as a zonal peak with a plateau region. The unbound drug concentration was determined as the drug concentration in the plateau. As low as 0.3 nM unbound CS-045 was determined with good reproducibility. It was found that CS-045 strongly binds with HSA, and the bound fraction in the 550 microM HSA solution was 99.93%, which was very close to that in human plasma (99.89%). The bound fractions were constant within the total drug concentration range of 1-10 microM in the HSA solution and 250 nM-10 microM in human plasma.

Chromans↗
PubMed2004

Increased expression and activity of 11beta-HSD-1 in diabetic islets and prevention with troglitazone.

To determine if increased local production of glucocorticoids by the pancreatic islets might play a role in the spontaneous noninsulin-dependent diabetes mellitus of obesity, we compared islet 11beta-HSD-1 mRNA and activity in islets of obese prediabetic and diabetic Zucker Diabetic Fatty (ZDF) (fa/fa) rats and lean wild-type (+/+) controls. In diabetic rat islets, both mRNA and enzymatic activity of the enzyme were increased in proportion to the hyperglycemia. Troglitazone (TGZ) treatment, beginning at 6 weeks of age, prevented the hyperglycemia, the hyperlipidemia, and the increase in 11beta-HSD-1. To determine if the metabolic abnormalities had caused the 11beta-HSD-1 increase, prediabetic islets were cultured in high or low glucose or in 2:1 oleate:palmitate for 3 days. Neither nutrient enhanced the expression of 11beta-HSD-1. We conclude that 11beta-HSD-1 expression and activity are increased in islets of diabetic, but not prediabetic ZDF rats, and that TGZ prevents both the increase in 11beta-HSD-1 and the diabetes.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2006

Phorbol ester potentiates the growth inhibitory effects of troglitazone via up-regulation of PPARgamma in A549 cells.

The activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to induce growth arrest and differentiation of various cancer cells. In the current study, we investigated the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the expression of PPARgamma and proliferation of A549 cells. TPA elicited a dose- and time-dependent increase in PPARgamma mRNA and protein levels. PPARgamma expression in response to TPA was attenuated by pretreatment with bisindolylmaleimide I, N-acetyl-L-cysteine (NAC) and PD98059. TPA-induced protein kinase C (PKC) activation was linked to the generation of reactive oxygen species (ROS), both of which were indispensable for PPARgamma expression in A549 cells. Pretreatment with bisindolylmaleimide I or NAC blocked TPA-induced phosphorylation of extracellular signal-regulated kinase (ERK), suggesting that ERK-mediated signaling is also involved in the induction of PPARgamma. Furthermore, the growth inhibitory effect of troglitazone was significantly potentiated by prolonged incubation with TPA and was attenuated in the presence of GW9662, a specific inhibitor of PPARgamma. These effects were associated with an induction of cell cycle arrest at G0/G1 phase, which was accompanied by the induction of p21Waf1/Cip1 expression and decreased cyclin D1 expression. Taken together, these observations indicate that TPA synergizes with PPARgamma ligand to inhibit cell growth through up-regulation of PPARgamma expression.

Antineoplastic Agents↗
PubMed2006

Synthetic peroxisome proliferator-activated receptor gamma agonists rosiglitazone and troglitazone suppress transcription by promoter 3 of the human thromboxane A2 receptor gene in human erythroleukemia cells.

The human thromboxane (TX)A2 receptor (TP) gene encodes two TP isoforms, TPalpha and TPbeta, that are regulated by distinct promoters designated promoter Prm1 and Prm3, respectively. Previous studies established that 15d-Delta12,14-prostaglandin J2 (15d-PGJ2) selectively inhibits Prm3 activity and TPbeta expression through a peroxisome proliferator-activated receptor (PPAR)gamma mechanism without affecting Prm1 activity or TPalpha expression in human megakaryocytic erythroleukemia (HEL) 92.1.7 cells. Herein, we investigated the effect of synthetic thiazolidinedione (TZD) PPARgamma ligands rosiglitazone and troglitazone on TP gene expression in HEL cells. Like 15d-PGJ2, both TZDs suppressed Prm3 activity, TPbeta mRNA expression and TP-mediated calcium mobilization without affecting Prm1 or TPalpha mRNA expression. However, unlike 15d-PGJ2, both TZDs mediated their PPARgamma-dependent effects through trans-repression of an activator protein-1 (AP-1) element, a site previously found to be critical for basal Prm3 activity. These data provide further evidence for the role of PPARgamma in regulating the human TP gene; they highlight further differences in TPalpha and TPbeta expression/regulation and point to essential differences between natural and synthetic PPARgamma agonists in mediating those effects.

Cell Line↗
PubMed2006

Synergistic effects of troglitazone in combination with cytotoxic agents in acute myelogenous leukaemia cells.

We have previously shown that troglitazone (TG) induces apoptosis in acute myelogenous leukaemia (AML) cell lines. Here we show that normal bone marrow and mobilized peripheral blood progenitors are highly resistant to TG at concentrations up to 100 microM, while primary cultures of AML bone marrow show significant decline in viability at >7.5 microM TG. The combination of standard cytotoxic agents (daunorubicin, etoposide, and cytarabine) with TG is synergistic in six AML cell lines, with the strongest synergy being exhibited when cells are pretreated with TG for 24h prior to addition of the cytotoxic agent. Significant declines in IC(50) for the cytotoxic agents are seen at nanomolar concentrations of TG. The in vitro synergy between TG and the cytotoxic drugs used in AML therapy provides a basis for in vivo evaluation of these combinations.

Apoptosis↗
PubMed2004

Unliganded RXR acts as an inhibitory factor on troglitazone-induced activation.

Troglitazone (TZ), a thiazolidinedione derivative, is a specific ligand for the peroxisome proliferator-activated receptor (PPAR) gamma and improves insulin sensitivity. PPARgamma regulates the expression of genes by binding to PPAR response element in promoter regions of regulator genes as heterodimers with a retinoid X receptor (RXR). We report here that PPARgamma activation by TZ depends on the expression levels of RXR. A transient transfection study in CV-1 cells revealed that the activation by TZ was suppressed by increasing amounts of expression of RXR, but not PPARgamma. Northern blot analysis revealed that PPARgamma and RXR were not expressed in CV-1 cells, and TZ did not induce PPARgamma or RXR mRNA in CV-1 cells indicating that RXR suppression is not related to these endogenous receptor expressions. Electrophoretic mobility shift assay revealed that the increasing amount of RXR did not compete with the DNA binding of the PPARgamma/RXR heterodimer in the presence or absence of TZ. Transfected co-activators enhanced the TZ-dependent gene transcription, and this activation was inhibited by excessive amounts of RXR, indicating that unliganded RXR may recruit the specific coactivators from the PPARgamma/RXR heterodimer.

Animals↗
PubMed2005

Effect of troglitazone on the desaturases in a rat model of insulin-resistance induced by a sucrose-rich diet.

A sucrose-rich diet generates time-dependent metabolic disorders similar to those found in diabetes type 2. After 8 month (mo) this diet evoked in the rat an increase of blood glucose, free fatty acids (FFA) and triacylycerides (TG) without insulin modification, an interruption of liver stearoyl-CoA desaturase-1 (SCD-1) mRNA and activity increase found at 6 mo, and an enhacement of Delta6 and Delta5 desaturase mRNA and Delta6 activity. We found that the administration of troglitazone (TRO), a peroxisome-proliferator-activated receptors gamma (PPAR-gamma) agonist, for 2 mo normalized plasma FFA, TG, and glucose without altering the insulinemia. It depressed liver SCD-1 mRNA in both control and sucrose-fed rats, decreasing the 18:1n-9/18:0 ratio in serum and liver lipids, and eliminated the increasing effect on mRNA and activity of Delta6 and Delta5 desaturases. These findings evidence again that desaturases are not affected through an insulin resistant effect evoked by the sucrose-rich diet and TRO recovers the altered metabolic plasma parameters as it corresponds to a PPAR-gamma agonist, but its effect on hepatic desaturases can not be attributed to a direct action on liver by PPAR-gamma, insulin, and even by an insulin sensitizing mechanism, suggesting it would be evoked indirectly through hepatic PPAR-alpha deactivation induced by the FFA decrease.

Animals↗