Effects Of Peroxisome Proliferator-activated Receptor Research Articles

Anti-proliferative effect of peroxisome proliferator-activated receptor ?? agonists on human malignant melanoma cells in vitro

Malignant melanoma has a poor reputation for early spread and no curative treatment is yet available. As peroxisome proliferator-activated receptor gamma (PPARgamma) agonists (glitazones) have recently been shown to have growth-inhibiting effects on different cancer lineages, the aim of this study was to analyze the effects of four glitazones (rosiglitazone, ciglitazone, pioglitazone and troglitazone) on the growth of six human malignant melanoma cells in vitro. Proliferation of six human melanoma cell lines under glitazone treatment over a broad concentration range (0.15-300 micromol/l) was assessed by means of the XTT cell proliferation assay, and expression of PPARgamma in these cell lines was analyzed using both immunohistochemical and molecular biological techniques. All four glitazones showed a significant dose-dependent anti-proliferative effect on all six cell lines starting at a concentration of 0.3 micromol/l, with ciglitazone being the most potent inhibitor of cell growth, followed by troglitazone, rosiglitazone and pioglitazone. PPARgamma was predominantly localized in the cytoplasm; however, there were quantitative differences in PPARgamma expression between the different cell lines as demonstrated by quantification of Western blots. As an already approved class of drugs, glitazones have been found to significantly inhibit growth of human malignant melanoma cells in vitro and might be a promising tool for further therapeutic studies.

Topical treatment with thiazolidinediones, activators of peroxisome proliferator‐activated receptor‐γ, normalizes epidermal homeostasis in a murine hyperproliferative disease model

In a murine model of epidermal hyperplasia reproducing some of the abnormalities of several common skin disorders, we previously demonstrated the antiproliferative and pro-differentiating effects of peroxisome proliferator-activated receptor (PPAR)alpha, PPARbeta/delta, and liver X receptor activators. Unlike other subgroups of PPAR activators, thiazolidinediones (TZDs), a family of PPARgamma ligands, did not inhibit keratinocyte proliferation in normal murine skin. Here, we studied the effects of two TZDs, namely ciglitazone (10 mM) and troglitazone (1 mM), in the same murine model where epidermal hyperproliferation was reproduced by repeated barrier abrogation with tape stripping. Topical treatment with ciglitazone and troglitazone resulted in a marked and significant decrease in epidermal thickness. Furthermore, in all TZD-treated groups, we observed a significant decrease in keratinocyte proliferation using proliferating cell nuclear antigen, 5-bromo-2'-deoxyuridine, and tritiated thymidine incorporation. However, using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, we found no difference in apoptosis between different treatments, emphasizing that it is the antiproliferative role of these activators that accounts for the decrease of epidermal thickness. Finally, using immunohistochemical methods, we determined the effects of ciglitazone on keratinocyte differentiation in this hyperproliferative model. We observed an increased expression of involucrin and filaggrin following ciglitazone treatment, suggesting a pro-differentiating action of TZDs in this model. In summary, topical TZDs significantly reduce epidermal keratinocyte proliferation while promoting differentiation in a murine model of hyperproliferative epidermis. Together, these results suggest that in addition to their metabolic effects currently in use in the treatment of type 2 diabetes, topical TZDs could be considered as potential alternative therapeutic agents in hyperproliferative skin diseases such as psoriasis.

PPAR-γ inhibits ANG II-induced cell growth via SHIP2 and 4E-BP1

The present study evaluated the effects of peroxisome proliferator-activated receptor (PPAR)-γ activators on ANG II-induced signaling pathways and cell growth. Vascular smooth muscle cells (VSMC) derived from rat mesenteric arteries were treated with ANG II, with/without the AT1 receptor blocker valsartan or the AT2 receptor blocker PD-123319, after pretreatment for 24 h with the PPAR-γ activators 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) or rosiglitazone. Both 15d-PGJ2 and rosiglitazone decreased ANG II-induced DNA synthesis. Rosiglitazone treatment increased nuclear PPAR-γ expression and activity in VSMC. However, rosiglitazone did not alter expression of PPAR-α/β, ERK 1/2, Akt, or ANG II receptors. 15d-PGJ2 and rosiglitazone decreased ERK 1/2 and Akt peak activity, both of which were induced by ANG II via the AT1 receptor. Rosiglitazone inhibited ANG II-enhanced phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), as well as Src homology (SH) 2-containing inositol phosphatase 2 (SHIP2). PPAR-γ activation reduced ANG II-induced growth associated with inhibition of ERK 1/2, Akt, 4E-BP1, and SHIP2. Modulation of these pathways by PPAR-γ activators may contribute to regression of vascular remodeling in hypertension.

Role of interaction between variants in the PPARG and interleukin-6 genes on obesity related metabolic risk factors

The combined effect of Peroxisome proliferator-activated receptor γ (PPARG) Pro/Ala and interleukin-6 G174C gene variants, was evaluated in 429 Caucasian subjects in order to determine whether subjects carrying both variants were at different risk for obesity. In particular, the combined contribution of these two variants (both independent and interaction effects) to the total variation of obesity-related factors was estimated. All subjects were genotyped for codon 12 Pro/Ala locus variability and for the interleukin-6- 174 C/G promoter polymorphism. Subjects with the Ala variant had significantly lower BMI, insulin resistance, triglyceride levels than those without. Furthermore, subjects with Ala variant had significantly lower IL-6 levels (0.88±0.9 vs 1.61±2.25 pg/ml; p=0.041). In contrast, the IL6- C variant was significantly associated with lower plasma IL-6 and with lower total cholesterol levels but was not significantly associated with any other obesity risk factors. Indeed, subjects carrying both PPARG and IL-6 gene variants, had a clearly more favourable profile of obesity related risk factors than subjects with one variant, having Ala+/C+ carriers lower BMI (22.8±2.3 vs 24.14±1.9; f=5.31; p<0.005), insulin resistance (1.49±0.70 vs 2.13±0.92; f=4.342; p=0.038) and triglyceride levels (79.15±32.9 vs 98±6.73 mg/dl; f=3.120; p<0.005). These findings suggest that the effect of the two genetic variants on ‘obesity related’ factors is additive.

The effect of PPAR γ ligands on the adipose tissue in insulin resistance

Insulin resistance is frequently accompanied by obesity and both obesity and type 2 diabetes are associated with a mild chronic inflammation. Elevated levels of various cytokines, such as TNF- α and IL-6, are typically found in the adipose tissue in these conditions. It has been suggested that many cytokines produced in the adipose tissue are derived from infiltrated inflammatory cells. However, the adipose tissue itself has proven to be an important endocrine organ, secreting several hormones and cytokines, usually referred to as adipokines. Peroxisome proliferator-activated receptor (PPAR) γ is essential for adipocyte proliferation and differentiation. In recent years, PPAR γ and its ligands, the thiazolidinediones (TZD), have achieved great attention due to their insulin sensitizing and anti-inflammatory properties. Treatment with TZDs result in improved insulin signaling and adipocyte differentiation, increased adipose tissue influx of free fatty acids and inhibition of cytokine expression and action. As a result, PPAR γ plays a central role in maintaining a functional and differentiated adipose tissue.

PPAR-alpha activators suppress STAT1 inflammatory signaling in lipopolysaccharide-activated rat glia

Signal transducers and activators of transcription (STATs) have recently been reported to mediate glial activation, and thus potentially play important roles in many neuroinflammatory diseases. We examined the effect of peroxisome proliferator-activated receptor (PPAR) activators on inflammatory responses in cultured rat brain glial cells. Four PPAR-alpha activators were tested, three fibrates (WY14643, clofibrate and fenofibrate) and an arachidonic acid derivative (5,8,11,14-eicosatetraynoic acid). We found that all four PPAR-alpha activators suppressed lipopolysaccharide-stimulated STAT1 phosphorylation and nuclear factor binding to gamma-interferon-activated sequence/interferon-alpha-stimulated response element sites known to contain STAT binding sites. PPAR-alpha activators also suppressed lipopolysaccharide-stimulated tumor necrosis factor-alpha and monocyte chemoattractant protein-1 transcription and release. These results suggest that PPAR-alpha activators may be useful in the treatment of inflammatory brain diseases.

Review: Vascular protective effects of peroxisome proliferator-activated receptor agonists

ardiovascular disease is significantly increased in patients with the metabolic syndrome and type 2 diabetes. A clustering of risk factors, including dyslipidaemia, insulin resistance, hypertension, inflammation and coagulation disorders are acting in concert to promote cardiovascular events in these patients. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that influence vascular function by altering gene expression in vascular tissue and indirectly via effects on other tissues. Indeed, PPAR activation displays beneficial effects on glucose homeostasis and lipid metabolism, and also on endothelial function and vessel wall inflammation. Clinically used PPARα agonists, such as fibrates, and PPARγ agonists, such as insulin-sensitising thiazolidinediones, may consequently alter the process of atherosclerosis, especially in subjects with the metabolic syndrome and type 2 diabetes. The present review highlights emerging evidence for beneficial effects of PPAR α and PPARγ in the prevention and treatment of atherosclerosis in such high-risk patients.

The effects of PPAR-? ligand pioglitazone on platelet aggregation and arterial thrombus formation

It has been suggested that peroxisome proliferator-activated receptor (PPAR)-gamma ligands reduce the development of atherosclerosis and myocardial ischemia-reperfusion injury; both of these phenomena are associated with platelet activation. We postulated that PPAR-gamma activation would inhibit platelet activation and intra-arterial thrombus formation. Sprague-Dawley rats were fed chow mixed with pioglitazone (1 or 10 mg/kg/day) for 7 to 10 days. A filter soaked in 30% FeCl(3) was applied around the abdominal aorta to study the patterns of arterial thrombogenesis. The aortic blood flow was continuously monitored using an ultrasonic Doppler flow probe. ADP and arachidonic acid-induced platelet aggregation and the expression of constitutive nitric oxide synthase (cNOS) and thrombomodulin in aorta were measured. Pioglitazone feeding delayed the time to occlusive thrombus formation by 40% (P<0.01 vs. control, n=9) without affecting the weight of the thrombus. ADP- as well as arachidonic acid-induced platelet aggregation was also inhibited by pioglitazone feeding (P<0.01 vs. control, n=9). Pioglitazone feeding also upregulated the aortic expression of cNOS and thrombomodulin; both are considered important factors in platelet aggregation and thrombus formation in vivo. The effect of a high dose (10 mg/kg/day) of pioglitazone was not more potent than that of a low dose (1 mg/kg/day). These results indicate that pioglitazone administration decreases platelet aggregation and delays intra-arterial thrombus formation in rats, at least partially, by an increase in the expression of cNOS and thrombomodulin.

Pioglitazone, a peroxisome proliferator-activated receptor γ activator, ameliorates experimental autoimmune myocarditis by modulating Th1/Th2 balance

Objectives – The aim of this study is to investigate the effect of Peroxisome proliferator-activated receptor γ (PPARγ) ligand on experimental autoimmune myocarditis (EAM). Background – Rat EAM model resembles the giant cell myocarditis in human. Recent studies have suggested that Th1 cytokines are involved in the initiation and progression of EAM, whereas Th2 cytokines are associated with the remission. PPARγ, which is a member of nuclear hormone receptor superfamily, has been known to affect not only glucose homeostasis but also immune responses, by regulating the Th1/Th2 balance. Methods – Lewis rats were immunized with cardiac myosin and divided into three groups: Group N, normal control rats ( n = 16); Group E, EAM rats ( n = 17); and Group P, EAM rats treated with a PPARγ activator pioglitazone ( n = 20). Results – Cardiac dysfunction and remodeling were inhibited in Group P compared to Group E. Heart weight/body weight ratio and the degree of inflammation and fibrosis were significantly lower in Group P than in Group E. The mRNA levels of macrophage inflammatory protein-1α (MIP-1α), which plays an important role in the recruitment of inflammatory cells in the early stage of EAM, were upregulated in the heart of Group E, but not in the heart of Group P. Furthermore, the treatment with pioglitazone decreased the expression levels of proinflamatory cytokine (TNFα and IL-1β) genes and Th1 cytokine (IFN-γ) genes, and increased the expression levels of Th2 cytokine (IL-4) gene. Conclusions – PPARγ ligands may have beneficial effects on myocarditis by inhibiting MIP-1α expression and modulating the Th1/Th2 balance.

Thiazolidinediones inhibit apoptosis and heat shock protein 60 expression in human vascular endothelial cells

This study evaluated direct effects of peroxisome proliferatoractivated receptor gamma(PPARgamma) agonists, including thiazolidinediones (TZDs), on vascular cell apoptosis and related protein expression to test the hypothesis that these effects are dependent on i) the respective agent's structure and ii) endothelial cells' vascular origin. Exposure (48 h) of human umbilical vein endothelial cells (HUVECs, n=6) to up to 10 microM troglitazone (TRO), rosiglitazone, pioglitazone, and to up to 50 microM RWJ241947=MCC-555 (RWJ) inhibited (p<0.05) apoptosis by 8-25%, whereas 15-deoxy-Delta(12-14)-prostaglandin J(2) (PGJ(2)) triggered (50 microM: + 400%, p<0.05) endothelial cell death versus control (=100%). Moreover, RWJ (50 microM) completely abrogated TNF-alpha(2000 U/ml) and stearic acid (200 microM) induced apoptosis in HUVECs . Similar results were obtained in human adult (saphenous) vein- and aortic endothelial cells, the latter showing no anti-apoptotic response to TRO. In HUVECs, TZDs' anti-apoptotic effects inversely correlated (r=-0.95, p<0.01) with increased (p<0.05) expression of the apoptosis-inhibitor bcl-2, whereas PGJ(2)-induced apoptosis was associated with upregulation of c-myc (+447%) and E2F-1 (+339%). Additionally, TZDs (by 25-39%) and PGJ(2) (-70%) reduced (p<0.05) expression of heat shock protein 60 (hsp60) showing no correlation with apoptosis (r=0.14, n.s.). Modulation of apoptosis by PPARgammaagonists differs in endothelial cells dependent on their vascular origin and the agonists' structure. Thiazolidinediones' ability to reduce both, endothelial apoptosis and hsp60 expression could well add to beneficial vascular effects attributed to these oral antidiabetic drugs.

Effect of peroxisome proliferator-activated receptor γ agonist, rosiglitazone, on dedifferentiated thyroid cancers

As genetic alterations in the gene for the peroxisome proliferator-activated receptor gamma (PPARgamma) have been described and PPAR agonists have been shown to redifferentiate thyroid cancers in animal models, we performed a pilot study in five patients with thyroglobulin-positive and I scan-negative thyroid cancers using the PPARgamma agonist rosiglitazone. Although thyroglobulin levels increased in four of the five patients after 3 months of treatment with rosiglitazone, the I scan remained negative in four patients and became only faintly positive in one patient for two lung metastases that could be correlated with metabolically active lung metastases shown by F-fluorodeoxyglucose positron emission tomography (F-FDG PET) and by computed tomography (CT). F-FDG PET, performed in four patients, revealed metastases of significant size in two patients, including the patient mentioned above and in a second patient confirmed by surgery. Treatment with rosiglitazone increased the production of thyroglobulin in some patients with thyroid cancers, but only rarely restored scintigraphically significant iodine trapping. It remains to be shown whether longer treatment periods might result in a more efficient redifferentiating effect.

Haploid inactivation of the amplified-in-breast cancer 3 coactivator reduces the inhibitory effect of peroxisome proliferator-activated receptor gamma and retinoid X receptor on cell proliferation and accelerates polyoma middle-T antigen-induced mammary tumorigenesis in mice.

The amplified-in-breast cancer 3 (AIB3) is a nuclear receptor coactivator amplified and overexpressed in human breast cancers. AIB3(-/-) mice die during gestation, whereas AIB3(+/-) mice exhibit normal development. Here, we demonstrate that AIB3 protein is mainly located in the nuclei of mammary epithelial cells and tumor cells and its levels are elevated in mammary epithelial cells at middle pregnant stage and in mammary tumor cells. To examine whether AIB3 reduction affects mammary tumorigenesis, we generated wild-type mouse mammary tumor virus/polyoma middle-T (WT/PyMT) and AIB3(+/-)/PyMT mice. Mammary tumor development in AIB3(+/-)/PyMT female and male mice was substantially accelerated compared with that in WT/PyMT mice, because of increased cell proliferation in early tumorigenic lesions, including ductal hyperplasia and mammary intraepithelial neoplasia. Tumor formation in nude mice that received premalignant AIB3(+/-)/PyMT mammary tissue was much faster than in nude mice that received transplants of premalignant WT/PyMT mammary tissue, which indicated that the accelerated tumorigenesis in AIB3(+/-)/PyMT mammary glands is due to a mammary epithelial autonomous defect. Expression of PyMT, estrogen receptor alpha and estrogen receptor alpha-regulated genes was unaffected in AIB3(+/-)/PyMT mammary glands, which suggests that the acceleration of mammary tumor formation in AIB3(+/-)/PyMT mice was not a consequence of changes in PyMT expression or in estrogen receptor function. Importantly, the inhibitory effects of peroxisome proliferator-activated receptor gamma (PPARgamma) and retinoid-X receptor (RXR) ligands on AIB3(+/-)/PyMT cell proliferation and the transcriptional function of PPARgamma in AIB3(+/-)/PyMT cells were reduced. Thus, AIB3 haplodeficiency may facilitate PyMT-induced tumorigenesis through a partial impairment of PPARgamma and RXR function. These results suggest that AIB3 may be a tumor suppressor that is required for the inhibition of cell proliferation by PPARgamma and RXR.

WY-14643 and 9-cis-retinoic acid induce IRS-2/PI 3-kinase signalling pathway and increase glucose transport in human skeletal muscle cells: differential effect in myotubes from healthy subjects and Type 2 diabetic patients

To determine the effects of peroxisome proliferator-activated receptor alpha (PPARalpha) and retinoid X receptor (RXR) agonists on insulin action, we investigated the effects of Wy-14643 and 9- cis-retinoic acid (9- cis-RA) on insulin signalling and glucose uptake in human myotubes. Primary cultures of differentiated human skeletal muscle cells, established from healthy subjects and Type 2 diabetic patients, were used to study the effects of Wy-14643 and 9- cis-RA on the expression and activity of proteins involved in the insulin signalling cascade. Glucose transport was assessed by measuring the rate of [(3)H]2-deoxyglucose uptake. Wy-14643 and 9- cis-RA increased IRS-2 and p85alpha phosphatidylinositol 3-kinase (PI 3-kinase) mRNA and protein expression in myotubes from non-diabetic and Type 2 diabetic subjects. This resulted in increased insulin stimulation of protein kinase B phosphorylation and increased glucose uptake in cells from control subjects. Myotubes from diabetic patients displayed marked alterations in the stimulation by insulin of the IRS-1/PI 3-kinase pathway. These alterations were associated with blunted stimulation of glucose transport. Treatment with Wy-14643 and 9- cis-RA did not restore these defects but increased the basal rate of glucose uptake. These results demonstrate that PPARalpha and RXR agonists can directly affect insulin signalling in human muscle cells. They also indicate that an increase in the IRS-2/PI 3-kinase pathway does not overcome the impaired stimulation of the IRS-1-dependent pathway and does not restore insulin-stimulated glucose uptake in myotubes from Type 2 diabetic patients.

Effects of peroxisome proliferator-activated receptor α activation on pathways contributing to cholesterol homeostasis in rat hepatocytes

Peroxisome proliferator-activated receptor alpha (PPARα) activation by fibrates controls expression of several genes involved in hepatic cholesterol metabolism. Other genes could be indirectly controlled in response to changes in cellular cholesterol availability. To further understand how fibrates may affect cholesterol synthesis, we investigated in parallel the changes in the metabolic pathways contributing to cholesterol homeostasis in liver. Ciprofibrate increased HMG-CoA reductase and FPP synthase mRNA levels in rat hepatocytes, together with cholesterogenesis from [ 14C] acetate and [ 3H] mevalonate. The up-regulation observed in fenofibrate- and WY-14,643-treated mice was abolished in PPARα-null mice, showing an essential role of PPARα. Among the three sterol regulatory element-binding protein (SREBP) mRNA species, only SREBP-1c level was significantly increased. In ciprofibrate-treated hepatocytes, cholesterol efflux was decreased, in parallel with cholesteryl ester storage and bile acids synthesis. As expected, AOX expression was strongly induced, supporting evidence of the peroxisome proliferation. Taken together, these results show that fibrates can cause cholesterol depletion in hepatocytes, possibly in part as a consequence of an important requirement of cholesterol for peroxisome proliferation, and increase cholesterogenesis by a compensatory phenomenon afterwards. Such cholesterogenesis regulation could occur in vivo, in species responsive to the peroxisome proliferative effect of PPARα ligands.

Effects of peroxisome proliferator-activated receptor $alpha; activation on pathways contributing to cholesterol homeostasis in rat hepatocytes

Effects of peroxisome proliferator-activated receptor $alpha; activation on pathways contributing to cholesterol homeostasis in rat hepatocytes

Peroxisome proliferator-activated receptor (PPAR)-alpha activation prevents diabetes in OLETF rats: comparison with PPAR-gamma activation.

Lipid accumulation in nonadipose tissues is closely related to the development of type 2 diabetes in obese subjects. We examined the potential preventive effect of peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma stimulation on the development of diabetes in obese diabetes-prone OLETF rats. Chronic administration of a PPAR-alpha agonist (0.5% [wt/wt] fenofibrate) or a PPAR-gamma agonist (3 mg x kg(-1) x day(-1) rosiglitazone) completely prevented the development of glycosuria. Pancreatic islets from untreated OLETF rats underwent sequential hypertrophy and atrophy, which was completely prevented by chronic fenofibrate treatment. In contrast, rosiglitazone treatment did not affect islet hypertrophy at earlier stages but prevented beta-cell atrophy at later stages. Fenofibrate treatment decreased body weight and visceral fat, whereas rosiglitazone treatment increased body weight. Despite the opposite effects on adiposity, both drugs were equally effective in improving insulin actions in skeletal muscle. Furthermore, both drugs significantly decreased the triglyceride content in the soleus muscle and pancreatic islets. The present study demonstrates that the PPAR-alpha agonist fenofibrate prevents the development of diabetes in OLETF rats by reducing adiposity, improving peripheral insulin action, and exerting beneficial effects on pancreatic beta-cells.

The central role of fat and effect of peroxisome proliferator-activated receptor–γ on progression of insulin resistance and cardiovascular disease

Recent evidence suggests that progression of insulin resistance parallels progression of atherosclerosis. Fat plays an integral role in the development of type 2 diabetes and vascular injury. The balance of adipose-derived substances, including free fatty acids, tumor necrosis factor–α, leptin, adiponectin, and plasminogen activator inhibitor–1, determine both insulin action and the state of vascular inflammation. Peroxisome proliferator-activated receptor–γ (PPAR-γ) ligands promote the balance of these substances to enhance insulin-me-diated glucose uptake and decrease inflammation. PPAR-γ ligands reverse the major defect of the insulin resistance syndrome and have important effects that inhibit atherosclerosis, improve endothelial cell function, and attenuate inflammation. Although more research is needed, data suggest that PPAR-γ ligands may prevent the progression of insulin resistance to diabetes and endothelial dysfunction to atherosclerosis.

Effects of peroxisome proliferator-activated receptor-gamma agonists on central nervous system inflammation.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays a critical role in glucose and lipid metabolism. More recently, PPAR-gamma ligands have been reported to inhibit the expression of proinflammatory molecules by monocytes/macrophages. Of relevance to CNS disease is that PPAR-gamma agonists have been demonstrated to have similar effects on microglia. PPAR-gamma agonists also ameliorate experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. This Mini-Review summarizes the effects of PPAR-gamma agonists in mediating immune responses and the potential of these agonists in the treatment of inflammatory disorders of the CNS.

Effect of peroxisome proliferator-activated receptor gamma on thromboxane A 2 and prostaglandin E 2 production in macrophage cell lines

We studied the effect of peroxisome proliferator-activated receptor γ (PPARγ) activation on thromboxane A 2(TXA 2) and prostaglandin E 2(PGE 2) production in monocyte/macrophage cell lines. In present experiment, we used human peripheral blood monocyte (PBMC), monocyte-cell line THP-1 and mouse macrophage-like cell line RAW264.7. The expression of PPARγ is reported in PBMC and THP-1. Synthetic PPARγ ligands (troglitazone or BRL49653) inhibited TXA 2 production and enhanced PGE 2 production of PBMC and THP-1. When treated with 0.5–10μM of troglitazone, there were no significant changes of TXA 2 and PGE 2 production of RAW264.7 cells, which express very low levels of PPARγ. When RAW264.7 cells was transfected with PPARγ expression plasmid and treated with troglitazone, PPARγ was activated in a dose-dependent manner. In PPARγ-transfected RAW264.7, TXA 2 production was decreased and PGE 2 production was increased by troglitazone treatment. But it needs high concentration of troglitazone (10μM) for increasing PGE 2 production. These results suggest that PPARγ may have negative effect on TXA 2 production, and also have slightly positive effect on PGE 2 production of macrophage.

Fenofibrate lowers abdominal and skeletal adiposity and improves insulin sensitivity in OLETF rats

The effect of peroxisome proliferator-activated receptor (PPAR)-α activators on the liver is well established, but the other effects on muscle and adipose tissue about lipid metabolism and insulin sensitivity are not clear. We investigated whether PPAR-α activation affects adiposity of skeletal muscle as well as adipose tissue and improves insulin sensitivity in spontaneous type 2 diabetes model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Thirty-three weeks of aged, 20 male OLETF rats were divided into two groups. Control group ( n=10) was fed with chow and treatment group ( n=10) with chow contained fenofibrate for 7 weeks. At the age of 40 weeks, all rats were examined with MRI, intravenous glucose tolerance test, and then sacrificed for measurement of fat mass and RNA analyses. The total fat (the sum of subcutaneous, mesenteric, epididymal, and retroperitoneal fat pads) measured by dissection was significantly reduced in treatment group. The signal intensity of muscular adiposity was significantly decreased in treatment group. The mRNA levels of FAT/CD36 and mitochondrial carnitine palmitoyltransferase I (M-CPT I) in liver were remarkably increased. Fasting plasma insulin and leptin levels, insulin response after intravenous glucose loading and homeostasis model assessment insulin resistance (HOMA IR) index were lowered in treatment group. Fenofibrate increase mitochondrial fatty acid β-oxidation in liver but not in skeletal muscle and lower the plasma levels of triglyceride and free fatty acid. It might result in reduction of adiposity of truncal adipose tissue and skeletal muscle. We suggest that reduction of adiposity in trunk and skeletal muscle might improve insulin sensitivity.