PPAR Research http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Nutrigenomic Functions of PPARs in Obesogenic Environments Wed, 30 Nov 2016 07:26:16 +0000 http://www.hindawi.com/journals/ppar/2016/4794576/ Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that mediate the effects of several nutrients or drugs through transcriptional regulation of their target genes in obesogenic environments. This review consists of three parts. First, we summarize current knowledge regarding the role of PPARs in governing the development of white and brown/beige adipocytes from uncommitted progenitor cells. Next, we discuss the interactions of dietary bioactive molecules, such as fatty acids and phytochemicals, with PPARs for the modulation of PPAR-dependent transcriptional activities and metabolic consequences. Lastly, the effects of PPAR polymorphism on obesity and metabolic outcomes are discussed. In this review, we aim to highlight the critical role of PPARs in the modulation of adiposity and subsequent metabolic adaptation in response to dietary challenges and genetic modifications. Understanding the changes in obesogenic environments as a consequence of PPARs/nutrient interactions may help expand the field of individualized nutrition to prevent obesity and obesity-associated metabolic comorbidities. Soonkyu Chung, Young Jun Kim, Soo Jin Yang, Yunkyoung Lee, and Myoungsook Lee Copyright © 2016 Soonkyu Chung et al. All rights reserved. Transcriptome-Wide Analysis Reveals the Role of PPARγ Controlling the Lipid Metabolism in Goat Mammary Epithelial Cells Thu, 13 Oct 2016 11:00:37 +0000 http://www.hindawi.com/journals/ppar/2016/9195680/ To explore the large-scale effect of peroxisome proliferator-activated receptor (PPARG) in goat mammary epithelial cells (GMEC), an oligonucleotide microarray platform was used for transcriptome profiling in cells overexpressing PPARG and incubated with or without rosiglitazone (ROSI, a PPARγ agonist). A total of 1143 differentially expressed genes (DEG) due to treatment were detected. The Dynamic Impact Approach (DIA) analysis uncovered the most impacted and induced pathways “fatty acid elongation in mitochondria,” “glycosaminoglycan biosynthesis-keratan sulfate,” and “pentose phosphate pathway.” The data highlights the central role of PPARG in milk fatty acid metabolism via controlling fatty acid elongation, biosynthesis of unsaturated fatty acid, lipid formation, and lipid secretion; furthermore, its role related to carbohydrate metabolism promotes the production of intermediates required for milk fat synthesis. Analysis of upstream regulators indicated that PPARG participates in multiple physiological processes via controlling or cross talking with other key transcription factors such as PPARD and NR1H3 (also known as liver-X-receptor-α). This transcriptome-wide analysis represents the first attempt to better understand the biological relevance of PPARG expression in ruminant mammary cells. Overall, the data underscored the importance of PPARG in mammary lipid metabolism and transcription factor control. Hengbo Shi, Wangsheng Zhao, Changhui Zhang, Khuram Shahzad, Jun Luo, and Juan J. Loor Copyright © 2016 Hengbo Shi et al. All rights reserved. PPAR Gamma in Neuroblastoma: The Translational Perspectives of Hypoglycemic Drugs Wed, 05 Oct 2016 12:31:05 +0000 http://www.hindawi.com/journals/ppar/2016/3038164/ Neuroblastoma (NB) is the most common and aggressive pediatric cancer, characterized by a remarkable phenotypic diversity and high malignancy. The heterogeneous clinical behavior, ranging from spontaneous remission to fatal metastatic disease, is attributable to NB biology and genetics. Despite major advances in therapies, NB is still associated with a high morbidity and mortality. Thus, novel diagnostic, prognostic, and therapeutic approaches are required, mainly to improve treatment outcomes of high-risk NB patients. Among neuroepithelial cancers, NB is the most studied tumor as far as PPAR ligands are concerned. PPAR ligands are endowed with antitumoral effects, mainly acting on cancer stem cells, and constitute a possible add-on therapy to antiblastic drugs, in particular for NB with unfavourable prognosis. While discussing clinical background, this review will provide a synopsis of the major studies about PPAR expression in NB, focusing on the potential beneficial effects of hypoglycemic drugs, thiazolidinediones and metformin, to reduce the occurrence of relapses as well as tumor regrowth in NB patients. Serena Vella, Pier Giulio Conaldi, Tullio Florio, and Aldo Pagano Copyright © 2016 Serena Vella et al. All rights reserved. PPARγ in Bacterial Infections: A Friend or Foe? Wed, 28 Sep 2016 14:17:19 +0000 http://www.hindawi.com/journals/ppar/2016/7963540/ Peroxisome proliferator-activated receptor γ (PPARγ) is now recognized as an important modulator of leukocyte inflammatory responses and function. Its immunoregulatory function has been studied in a variety of contexts, including bacterial infections of the lungs and central nervous system, sepsis, and conditions such as chronic granulomatous disease. Although it is generally believed that PPARγ activation is beneficial for the host during bacterial infections via its anti-inflammatory and antibacterial properties, PPARγ agonists have also been shown to dampen the host immune response and in some cases exacerbate infection by promoting leukocyte apoptosis and interfering with leukocyte migration and infiltration. In this review we discuss the role of PPARγ and its activation during bacterial infections, with focus on the potential of PPARγ agonists and perhaps antagonists as novel therapeutic modalities. We conclude that adjustment in the dosage and timing of PPARγ agonist administration, based on the competence of host antimicrobial defenses and the extent of inflammatory response and tissue injury, is critical for achieving the essential balance between pro- and anti-inflammatory effects on the immune system. Aravind T. Reddy, Sowmya P. Lakshmi, and Raju C. Reddy Copyright © 2016 Aravind T. Reddy et al. All rights reserved. IL-15 Mediates Mitochondrial Activity through a PPARδ-Dependent-PPARα-Independent Mechanism in Skeletal Muscle Cells Wed, 21 Sep 2016 09:44:41 +0000 http://www.hindawi.com/journals/ppar/2016/5465804/ Molecular mediators of metabolic processes, to increase energy expenditure, have become a focus for therapies of obesity. The discovery of cytokines secreted from the skeletal muscle (SKM), termed “myokines,” has garnered attention due to their positive effects on metabolic processes. Interleukin-15 (IL-15) is a myokine that has numerous positive metabolic effects and is linked to the PPAR family of mitochondrial regulators. Here, we aimed to determine the importance of PPARα and/or PPARδ as targets of IL-15 signaling. C2C12 SKM cells were differentiated for 6 days and treated every other day with IL-15 (100 ng/mL), a PPARα inhibitor (GW-6471), a PPARδ inhibitor (GSK-3787), or both IL-15 and the inhibitors. IL-15 increased mitochondrial activity and induced PPARα, PPARδ, PGC1α, PGC1β, UCP2, and Nrf1 expression. There was no effect of inhibiting PPARα, in combination with IL-15, on the aforementioned mRNA levels except for PGC1β and Nrf1. However, with PPARδ inhibition, IL-15 failed to induce the expression levels of PGC1α, PGC1β, UCP2, and Nrf1. Further, inhibition of PPARδ abolished IL-15 induced increases in citrate synthase activity, ATP production, and overall mitochondrial activity. IL-15 had no effects on mitochondrial biogenesis. Our data indicates that PPARδ activity is required for the beneficial metabolic effects of IL-15 signaling in SKM. Shantaé M. Thornton, James E. Krolopp, and Marcia J. Abbott Copyright © 2016 Shantaé M. Thornton et al. All rights reserved. PPARγ as a Novel Therapeutic Target in Lung Cancer Tue, 06 Sep 2016 15:39:40 +0000 http://www.hindawi.com/journals/ppar/2016/8972570/ Lung cancer is the leading cause of cancer-related death, with more than half the patients having advanced-stage disease at the time of initial diagnosis and thus facing a poor prognosis. This dire situation poses a need for new approaches in prevention and treatment. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. Its involvement in adipocyte differentiation and glucose and lipid homeostasis is well-recognized, but accumulating evidence now suggests that PPARγ may also function as a tumor suppressor, inhibiting development of primary tumors and metastases in lung cancer and other malignancies. Besides having prodifferentiation, antiproliferative, and proapoptotic effects, PPARγ agonists have been shown to prevent cancer cells from acquiring the migratory and invasive capabilities essential for successful metastasis. Angiogenesis and secretion of certain matrix metalloproteinases and extracellular matrix proteins within the tumor microenvironment are also regulated by PPARγ. This review of the current literature highlights the potential of PPARγ agonists as novel therapeutic modalities in lung cancer, either as monotherapy or in combination with standard cytotoxic chemotherapy. Aravind T. Reddy, Sowmya P. Lakshmi, and Raju C. Reddy Copyright © 2016 Aravind T. Reddy et al. All rights reserved. Commonalities in the Association between PPARG and Vitamin D Related with Obesity and Carcinogenesis Mon, 08 Aug 2016 16:27:04 +0000 http://www.hindawi.com/journals/ppar/2016/2308249/ The PPAR nuclear receptor family has acquired great relevance in the last decade, which is formed by three different isoforms (PPARα, PPAR/δ, and PPAR ϒ). Those nuclear receptors are members of the steroid receptor superfamily which take part in essential metabolic and life-sustaining actions. Specifically, PPARG has been implicated in the regulation of processes concerning metabolism, inflammation, atherosclerosis, cell differentiation, and proliferation. Thus, a considerable amount of literature has emerged in the last ten years linking PPARG signalling with metabolic conditions such as obesity and diabetes, cardiovascular disease, and, more recently, cancer. This review paper, at crossroads of basic sciences, preclinical, and clinical data, intends to analyse the last research concerning PPARG signalling in obesity and cancer. Afterwards, possible links between four interrelated actors will be established: PPARG, the vitamin D/VDR system, obesity, and cancer, opening up the door to further investigation and new hypothesis in this fascinating area of research. Borja Bandera Merchan, Francisco José Tinahones, and Manuel Macías-González Copyright © 2016 Borja Bandera Merchan et al. All rights reserved. PPAR Ligands Function as Suppressors That Target Biological Actions of HMGB1 Tue, 02 Aug 2016 07:14:00 +0000 http://www.hindawi.com/journals/ppar/2016/2612743/ High mobility group box 1 (HMGB1), which has become one of the most intriguing molecules in inflammatory disorders and cancers and with which ligand-activated peroxisome proliferator-activated receptors (PPARs) are highly associated, is considered as a therapeutic target. Of particular interest is the fact that certain PPAR ligands have demonstrated their potent anti-inflammatory activities and potential anticancer effects. In this review article we summarize recent experimental evidence that PPAR ligands function as suppressors that target biological actions of HMGB1, including intracellular expression, receptor signaling cascades, and extracellular secretion of HMGB1 in cell lines and/or animal models. We also propose the possible mechanisms underlying PPAR involvement in inflammatory disorders and discuss the future therapeutic value of PPAR ligands targeting HMGB1 molecule for cancer prevention and treatment. Shibo Ying, Xiang Xiao, Tianhui Chen, and Jianlin Lou Copyright © 2016 Shibo Ying et al. All rights reserved. Peroxisome Proliferator-Activated Receptors in Female Reproduction and Fertility Sun, 31 Jul 2016 09:58:45 +0000 http://www.hindawi.com/journals/ppar/2016/4612306/ Reproductive functions may be altered by the exposure to a multitude of endogenous and exogenous agents, drug or environmental pollutants, which are known to affect gene transcription through the peroxisome proliferator-activated receptors (PPARs) activation. PPARs act as ligand activated transcription factors and regulate metabolic processes such as lipid and glucose metabolism, energy homeostasis, inflammation, and cell proliferation and differentiation. All PPARs isotypes are expressed along the hypothalamic-pituitary-gonadal axis and are strictly involved in reproductive functions. Since female fertility and energy metabolism are tightly interconnected, the research on female infertility points towards the exploration of potential PPARs activating/antagonizing compounds, mainly belonging to the class of thiazolidinediones (TZDs) and fibrates, as useful agents for the maintenance of metabolic homeostasis in women with ovarian dysfunctions. In the present review, we discuss the recent evidence about PPARs expression in the hypothalamic-pituitary-gonadal axis and their involvement in female reproduction. Finally, the therapeutic potential of their manipulation through several drugs is also discussed. Maurizio Vitti, Giovanna Di Emidio, Michela Di Carlo, Gaspare Carta, Andrea Antonosante, Paolo Giovanni Artini, Annamaria Cimini, Carla Tatone, and Elisabetta Benedetti Copyright © 2016 Maurizio Vitti et al. All rights reserved. PPAR in Cardiovascular Disorders Tue, 26 Jul 2016 08:25:21 +0000 http://www.hindawi.com/journals/ppar/2016/6293629/ Alexander N. Orekhov, Nigora Mukhamedova, Ekaterina A. Ivanova, and Manfredi Rizzo Copyright © 2016 Alexander N. Orekhov et al. All rights reserved. HDAC Inhibition Modulates Cardiac PPARs and Fatty Acid Metabolism in Diabetic Cardiomyopathy Thu, 30 Jun 2016 12:26:59 +0000 http://www.hindawi.com/journals/ppar/2016/5938740/ Peroxisome proliferator-activated receptors (PPARs) regulate cardiac glucose and lipid homeostasis. Histone deacetylase (HDAC) inhibitor has anti-inflammatory effects which may play a key role in modulating PPARs and fatty acid metabolism. The aim of this study was to investigate whether HDAC inhibitor, MPT0E014, can modulate myocardial PPARs, inflammation, and fatty acid metabolism in diabetes mellitus (DM) cardiomyopathy. Electrocardiography, echocardiography, and western blotting were used to evaluate the electrophysiological activity, cardiac structure, fatty acid metabolism, inflammation, and PPAR isoform expressions in the control and streptozotocin-nicotinamide-induced DM rats with or without MPT0E014. Compared to control, DM and MPT0E014-treated DM rats had elevated blood glucose levels and lower body weights. However, MPT0E014-treated DM and control rats had smaller left ventricular end-diastolic diameter and shorter QT interval than DM rats. The control and MPT0E014-treated DM rats had greater cardiac PPAR-α and PPAR-δ protein expressions, but less cardiac PPAR-γ than DM rats. Moreover, control and MPT0E014-treated DM rats had lower concentrations of 5′ adenosine monophosphate-activated protein kinase 2α, PPAR-γ coactivator 1α, phosphorylated acetyl CoA carboxylase, cluster of differentiation 36, diacylglycerol acyltransferase 1 (DGAT1), DGAT2, tumor necrosis factor-α, and interleukin-6 protein than DM rats. HDAC inhibition significantly attenuated DM cardiomyopathy through modulation of cardiac PPARS, fatty acid metabolism, and proinflammatory cytokines. Ting-I Lee, Yu-Hsun Kao, Wen-Chin Tsai, Cheng-Chih Chung, Yao-Chang Chen, and Yi-Jen Chen Copyright © 2016 Ting-I Lee et al. All rights reserved. Testosterone Replacement Modulates Cardiac Metabolic Remodeling after Myocardial Infarction by Upregulating PPARα Thu, 16 Jun 2016 08:55:09 +0000 http://www.hindawi.com/journals/ppar/2016/4518754/ Despite the importance of testosterone as a metabolic hormone, its effects on myocardial metabolism in the ischemic heart remain unclear. Myocardial ischemia leads to metabolic remodeling, ultimately resulting in ATP deficiency and cardiac dysfunction. In the present study, the effects of testosterone replacement on the ischemic heart were assessed in a castrated rat myocardial infarction model established by ligating the left anterior descending coronary artery 2 weeks after castration. The results of real-time PCR and Western blot analyses showed that peroxisome proliferator-activated receptor α (PPARα) decreased in the ischemic myocardium of castrated rats, compared with the sham-castration group, and the mRNA expression of genes involved in fatty acid metabolism (the fatty acid translocase CD36, carnitine palmitoyltransferase I, and medium-chain acyl-CoA dehydrogenase) and glucose transporter-4 also decreased. A decline in ATP levels in the castrated rats was accompanied by increased cardiomyocyte apoptosis and fibrosis and impaired cardiac function, compared with the sham-castration group, and these detrimental effects were reversed by testosterone replacement. Taken together, our findings suggest that testosterone can modulate myocardial metabolic remodeling by upregulating PPARα after myocardial infarction, exerting a protective effect on cardiac function. Jing Yang, Fengyue Wang, Weiju Sun, Yanli Dong, Mingyu Li, and Lu Fu Copyright © 2016 Jing Yang et al. All rights reserved. A Citrus bergamia Extract Decreases Adipogenesis and Increases Lipolysis by Modulating PPAR Levels in Mesenchymal Stem Cells from Human Adipose Tissue Wed, 15 Jun 2016 08:35:29 +0000 http://www.hindawi.com/journals/ppar/2016/4563815/ The aim of this research was to assess the impact of a well-characterized extract from Citrus bergamia juice on adipogenesis and/or lipolysis using mesenchymal stem cells from human adipose tissue as a cell model. To evaluate the effects on adipogenesis, some cell cultures were treated with adipogenic medium plus 10 or 100 μg/mL of extract. To determine the properties on lipolysis, additional mesenchymal stem cells were cultured with adipogenic medium for 14 days and after this time added with Citrus bergamia for further 14 days. To verify adipogenic differentiation, oil red O staining at 7, 14, 21, and 28 days was performed. Moreover, the expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), adipocytes fatty acid-binding protein (A-FABP), adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), monoglyceride lipase (MGL), 5′-adenosine monophosphate-activated protein kinase (AMPK)α1/2, and pAMPKα1/2 was evaluated by Western blot analysis and the release of glycerol by colorimetric assay. Citrus bergamia extract suppressed the accumulation of intracellular lipids in mesenchymal stem cells during adipogenic differentiation and promoted lipolysis by repressing the expression of adipogenic genes and activating lipolytic genes. Citrus bergamia extract could be a useful natural product for improving adipose mobilization in obesity-related disorders. Debora Lo Furno, Adriana Carol Eleonora Graziano, Rosanna Avola, Rosario Giuffrida, Vincenzo Perciavalle, Francesco Bonina, Giuliana Mannino, and Venera Cardile Copyright © 2016 Debora Lo Furno et al. All rights reserved. Pioglitazone Attenuates Drug-Eluting Stent-Induced Proinflammatory State in Patients by Blocking Ubiquitination of PPAR Tue, 14 Jun 2016 06:21:51 +0000 http://www.hindawi.com/journals/ppar/2016/7407153/ The inflammatory response after polymer-based drug-eluting stent (DES) placement has recently emerged as a major concern. The biologic roles of peroxisome proliferator-activated receptor- (PPAR-) activators thiazolidinedione (TZD) remain controversial in cardiovascular disease. Herein, we investigated the antiinflammatory effects of pioglitazone (PIO) on circulating peripheral blood mononuclear cells (MNCs) in patients after coronary DES implantation. Methods and Results. Twenty-eight patients with coronary artery disease and who underwent DES implantations were randomly assigned to pioglitazone (30 mg/d; PIO) or placebo (control; Con) treatment in addition to optimal standard therapy. After 12 weeks of treatment, plasma concentrations of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor- (TNF-), and matrix metalloproteinase-9 (MMP-9) were significantly decreased in PIO group compared to the Con group (, 0.011, 0.008, and 0.012, resp.). DES-induced mRNA expressions of IL-6, TNF-, and MMP-9 in circulating MNC were significantly blocked by PIO (, 0.012, and 0.007, resp.). In addition, PIO markedly inhibited DES-enhanced NF-κB function and DES-blocked PPAR- activity. Mechanically, DES induced PPAR- ubiquitination and degradation in protein level, which can be totally reversed by PIO. Conclusion. PIO treatment attenuated DES-induced PPAR loss, NF-κB activation, and proinflammation, indicating that PIO may have a novel direct protective role in modulating proinflammation in DES era. Zhongxia Wang, Tao Zhang, Lizhe Sun, Ruifeng Li, Yuanyuan Wei, Xiaojuan Fan, Zuyi Yuan, Junhui Liu, and Tao Chen Copyright © 2016 Zhongxia Wang et al. All rights reserved. PPARγ Agonists as an Anti-Inflammatory Treatment Inhibiting Rotavirus Infection of Small Intestinal Villi Mon, 13 Jun 2016 12:09:50 +0000 http://www.hindawi.com/journals/ppar/2016/4049373/ Rotavirus infection has been reported to induce an inflammatory response in the host cell accompanied by the increased expression or activation of some cellular molecules including ROS, NF-κB, and COX-2. PPARγ stimulation and N-acetylcysteine (NAC) treatment have been found to interfere with viral infections including rotavirus infection. Small intestinal villi isolated from in vivo infected mice with rotavirus ECwt were analyzed for the percentage of ECwt-infected cells, the presence of rotavirus antigens, and infectious virion yield following treatment with pioglitazone. Isolated villi were also infected in vitro and treated with PPARγ agonists (PGZ, TZD, RGZ, DHA, and ALA), all-trans retinoic acid (ATRA), and NAC. After treatments, the expression of cellular proteins including PPARγ, NF-κB, PDI, Hsc70, and COX-2 was analyzed using immunochemistry, ELISA, immunofluorescence, and Western blotting. The results showed that rotavirus infection led to an increased accumulation of the cellular proteins studied and ROS. The virus infection-induced accumulation of the cellular proteins studied and ROS was reduced upon pioglitazone treatment, causing also a concomitant reduction of the infectious virion yield. We hypothesized that rotavirus infection is benefiting from the induction of a host cell proinflammatory response and that the interference of the inflammatory pathways involved leads to decreased infection. Dory Gómez, Natalia Muñoz, Rafael Guerrero, Orlando Acosta, and Carlos A. Guerrero Copyright © 2016 Dory Gómez et al. All rights reserved. Pioglitazone Effect on Glioma Stem Cell Lines: Really a Promising Drug Therapy for Glioblastoma? Wed, 25 May 2016 11:26:05 +0000 http://www.hindawi.com/journals/ppar/2016/7175067/ Glioblastoma multiforme (GBM) represents one of the most frequent malignant brain tumors. Current therapies do not provide real solutions to this pathology. Their failure can be ascribed to a cell subpopulation with stem-like properties called glioma stem cells (GSCs). Therefore, new therapeutic strategies GSC-targeted are needed. PPARγ, a nuclear receptor involved in lipid metabolism, has already been indicated as a promising target for antineoplastic therapies. Recent studies have reported that synthetic PPARγ agonists, already in clinical use for the treatment of type II diabetes, exhibit antineoplastic effects in a wide range of malignant tumor cells, including glioma cells. We investigated the effect of the synthetic PPARγ agonist Pioglitazone on viability, proliferation, morphology, and differentiation in six GSC lines isolated from GBM patients. We also analyzed Pioglitazone-induced changes in transcriptional levels of Wnt/β catenin related genes. Results showed that response to Pioglitazone was heterogeneous inducing an evident decrease of cell viability and proliferation only in a subset of GSC lines. We did not find any sign of cell differentiation neither observing cell morphology nor analyzing the expression of stemness and differentiation markers. Moreover, Wnt/β signaling pathway was only mildly affected from a transcriptional point of view after Pioglitazone exposure. Chiara Cilibrasi, Valentina Butta, Gabriele Riva, and Angela Bentivegna Copyright © 2016 Chiara Cilibrasi et al. All rights reserved. Current Advances in the Biochemical and Physiological Aspects of the Treatment of Type 2 Diabetes Mellitus with Thiazolidinediones Mon, 23 May 2016 06:25:28 +0000 http://www.hindawi.com/journals/ppar/2016/7614270/ The present review summarizes the current advances in the biochemical and physiological aspects in the treatment of type 2 diabetes mellitus (DM2) with thiazolidinediones (TZDs). DM2 is a metabolic disorder characterized by hyperglycemia, triggering the abnormal activation of physiological pathways such as glucose autooxidation, polyol’s pathway, formation of advance glycation end (AGE) products, and glycolysis, leading to the overproduction of reactive oxygen species (ROS) and proinflammatory cytokines, which are responsible for the micro- and macrovascular complications of the disease. The treatment of DM2 has been directed toward the reduction of hyperglycemia using different drugs such as insulin sensitizers, as the case of TZDs, which are able to lower blood glucose levels and circulating triglycerides by binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) as full agonists. When TZDs interact with PPARγ, the receptor regulates the transcription of different genes involved in glucose homeostasis, insulin resistance, and adipogenesis. However, TZDs exhibit some adverse effects such as fluid retention, weight gain, hepatotoxicity, plasma-volume expansion, hemodilution, edema, bone fractures, and congestive heart failure, which limits their use in DM2 patients. D. Alemán-González-Duhart, F. Tamay-Cach, S. Álvarez-Almazán, and J. E. Mendieta-Wejebe Copyright © 2016 D. Alemán-González-Duhart et al. All rights reserved. Peroxisome Proliferator-Activated Receptor-γ Is Critical to Cardiac Fibrosis Thu, 12 May 2016 17:12:45 +0000 http://www.hindawi.com/journals/ppar/2016/2198645/ Peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily, which plays a central role in regulating lipid and glucose metabolism. However, accumulating evidence demonstrates that PPARγ agonists have potential to reduce inflammation, influence the balance of immune cells, suppress oxidative stress, and improve endothelial function, which are all involved in the cellular and molecular mechanisms of cardiac fibrosis. Thus, in this review we discuss the role of PPARγ in various cardiovascular conditions associated with cardiac fibrosis, including diabetes mellitus, hypertension, myocardial infarction, heart failure, ischemia/reperfusion injury, atrial fibrillation, and several other cardiovascular disease (CVD) conditions, and summarize the developmental status of PPARγ agonists for the clinical management of CVD. Huang-Jun Liu, Hai-Han Liao, Zheng Yang, and Qi-Zhu Tang Copyright © 2016 Huang-Jun Liu et al. All rights reserved. 15-Deoxy-Δ12,14-prostaglandin J2 Induces Apoptosis and Upregulates SOCS3 in Human Thyroid Cancer Cells Sun, 17 Apr 2016 12:14:31 +0000 http://www.hindawi.com/journals/ppar/2016/4106297/ The cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a natural ligand of peroxisome proliferator-activated receptor gamma (PPAR-γ) and a potential mediator of apoptosis in cancer cells. In the present study, we evaluated the effect of 15d-PGJ2 in human thyroid papillary carcinoma cells (TPC-1) using different doses of 15d-PGJ2 (0.6 to 20 μM) to determine IC50 (9.3 μM) via the MTT assay. The supernatant culture medium of the TPC-1 cells that was treated either with 15d-PGJ2 or with vehicle (control) for 24 hours was assessed for IL-6 secretion via CBA assay. RT-qPCR was used to evaluate mRNA expression of IL-6, SOCS1, SOCS3, and STAT3. TPC-1 cells treated with 15d-PGJ2 decreased the secretion and expression of IL-6 and STAT3, while it increased SOCS1 and SOCS3. Overall, we demonstrated that 15d-PGJ2 downregulated IL-6 signaling pathway and led TPC-1 cells into apoptosis. In conclusion, 15d-PGJ2 shows the potential to become a new therapeutic approach for thyroid tumors. Carlos Antônio Trindade-da-Silva, Carolina Fernandes Reis, Lara Vecchi, Marcelo Henrique Napimoga, Marcelo Sperandio, Bruna França Matias Colombo, Patrícia Terra Alves, Laura Sterian Ward, Carlos Ueira-Vieira, and Luiz Ricardo Goulart Copyright © 2016 Carlos Antônio Trindade-da-Silva et al. All rights reserved. Timcodar (VX-853) Is a Non-FKBP12 Binding Macrolide Derivative That Inhibits PPARγ and Suppresses Adipogenesis Thu, 14 Apr 2016 09:47:09 +0000 http://www.hindawi.com/journals/ppar/2016/6218637/ Nutrient overload and genetic factors have led to a worldwide epidemic of obesity that is the underlying cause of diabetes, atherosclerosis, and cardiovascular disease. In this study, we used macrolide drugs such as FK506, rapamycin, and macrolide derived, timcodar (VX-853), to determine their effects on lipid accumulation during adipogenesis. Rapamycin and FK506 bind to FK506-binding proteins (FKBPs), such as FKBP12, which causes suppression of the immune system and inhibition of mTOR. Rapamycin has been previously reported to inhibit the adipogenic process and lipid accumulation. However, rapamycin treatment in rodents caused immune suppression and glucose resistance, even though the mice lost weight. Here we show that timcodar (1 μM), a non-FKBP12-binding drug, significantly () inhibited lipid accumulation during adipogenesis. A comparison of the same concentration of timcodar (1 μM) and rapamycin (1 μM) showed that both are inhibitors of lipid accumulation during adipogenesis. Importantly, timcodar potently () suppressed transcriptional regulators of adipogenesis, PPARγ and C/EBPα, resulting in the inhibition of genes involved in lipid accumulation. These studies set the stage for timcodar as a possible antiobesity therapy, which is rapidly emerging as a pandemic. Terry D. Hinds Jr., Kezia John, Lucien McBeth, Christopher J. Trabbic, and Edwin R. Sanchez Copyright © 2016 Terry D. Hinds Jr. et al. All rights reserved. PPARgene: A Database of Experimentally Verified and Computationally Predicted PPAR Target Genes Mon, 11 Apr 2016 09:41:25 +0000 http://www.hindawi.com/journals/ppar/2016/6042162/ The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear receptor superfamily. Upon ligand binding, PPARs activate target gene transcription and regulate a variety of important physiological processes such as lipid metabolism, inflammation, and wound healing. Here, we describe the first database of PPAR target genes, PPARgene. Among the 225 experimentally verified PPAR target genes, 83 are for PPARα, 83 are for PPARβ/δ, and 104 are for PPARγ. Detailed information including tissue types, species, and reference PubMed IDs was also provided. In addition, we developed a machine learning method to predict novel PPAR target genes by integrating in silico PPAR-responsive element (PPRE) analysis with high throughput gene expression data. Fivefold cross validation showed that the performance of this prediction method was significantly improved compared to the in silico PPRE analysis method. The prediction tool is also implemented in the PPARgene database. Li Fang, Man Zhang, Yanhui Li, Yan Liu, Qinghua Cui, and Nanping Wang Copyright © 2016 Li Fang et al. All rights reserved. Pioglitazone Protected against Cardiac Hypertrophy via Inhibiting AKT/GSK3β and MAPK Signaling Pathways Sun, 27 Mar 2016 11:52:39 +0000 http://www.hindawi.com/journals/ppar/2016/9174190/ Peroxisome proliferator activated receptor γ (PPARγ) has been closely involved in the process of cardiovascular diseases. This study was to investigate whether pioglitazone (PIO), a PPARγ agonist, could protect against pressure overload-induced cardiac hypertrophy. Mice were orally given PIO (2.5 mg/kg) from 1 week after aortic banding and continuing for 7 weeks. The morphological examination and biochemical analysis were used to evaluate the effects of PIO. Neonatal rat ventricular cardiomyocytes were also used to verify the protection of PIO against hypertrophy in vitro. The results in our study demonstrated that PIO remarkably inhibited hypertrophic response induced by aortic banding in vivo. Besides, PIO also suppressed cardiac fibrosis in vivo. PIO treatment also inhibited the activation of protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β) and mitogen-activated protein kinase (MAPK) in the heart. In addition, PIO alleviated angiotensin II-induced hypertrophic response in vitro. In conclusion, PIO could inhibit cardiac hypertrophy via attenuation of AKT/GSK3β and MAPK pathways. Wen-Ying Wei, Zhen-Guo Ma, Si-Chi Xu, Ning Zhang, and Qi-Zhu Tang Copyright © 2016 Wen-Ying Wei et al. All rights reserved. Fenofibrate plus Metformin Produces Cardioprotection in a Type 2 Diabetes and Acute Myocardial Infarction Model Wed, 16 Mar 2016 10:00:10 +0000 http://www.hindawi.com/journals/ppar/2016/8237264/ We investigated whether fenofibrate, metformin, and their combination generate cardioprotection in a rat model of type 2 diabetes (T2D) and acute myocardial infarction (AMI). Streptozotocin-induced diabetic- (DB-) rats received 14 days of either vehicle, fenofibrate, metformin, or their combination and immediately after underwent myocardial ischemia/reperfusion (I/R). Fenofibrate plus metformin generated cardioprotection in a DBI/R model, reported as decreased coronary vascular resistance, compared to DBI/R-Vehicle, smaller infarct size, and increased cardiac work. The subchronic treatment with fenofibrate plus metformin increased, compared with DBI/R-Vehicle, total antioxidant capacity, manganese-dependent superoxide dismutase activity (MnSOD), guanosine triphosphate cyclohydrolase I (GTPCH-I) expression, tetrahydrobiopterin : dihydrobiopterin (BH4 : BH2) ratio, endothelial nitric oxide synthase (eNOS) activity, nitric oxide (NO) bioavailability, and decreased inducible NOS (iNOS) activity. These findings suggest that PPARα activation by fenofibrate + metformin, at low doses, generates cardioprotection in a rat model of T2D and AMI and may represent a novel treatment strategy to limit I/R injury in patients with T2D. Víctor Hugo Oidor-Chan, Enrique Hong, Francisca Pérez-Severiano, Sergio Montes, Juan Carlos Torres-Narváez, Leonardo del Valle-Mondragón, Gustavo Pastelín-Hernández, and Alicia Sánchez-Mendoza Copyright © 2016 Víctor Hugo Oidor-Chan et al. All rights reserved. Possible Role of Interaction between PPARα and Cyclophilin D in Cardioprotection of AMPK against In Vivo Ischemia-Reperfusion in Rats Tue, 08 Mar 2016 06:12:42 +0000 http://www.hindawi.com/journals/ppar/2016/9282087/ Activated AMPK protects the heart from cardiac ischemia-reperfusion (IR) injury and is associated with inhibition of mitochondrial permeability transition pore (PTP) opening. On the other hand, pharmacological inhibition of the PTP reduces infarct size and improves cardiac function. However, it is unclear whether beneficial effects of AMPK are mediated through the PTP and, if they are not, whether simultaneous activation of AMPK and inhibition of the PTP exert synergistic protective effects against cardiac IR injury. Here, we examined the effects of the AMPK activator, A-769662 in combination with the PTP inhibitor, sanglifehrin A (SfA) on in vivo cardiac IR. Cardiac dysfunction following IR injury was associated with decreased activity of the mitochondrial electron transport chain (ETC) and increased mitochondrial ROS and PTP opening. Administration of A-769662 or SfA individually upon reperfusion improved cardiac function, reduced infarction size, and inhibited ROS production and PTP opening. However, simultaneous administration of SfA and A-769662 did not provide synergistic improvement of postischemic recovery of cardiac and mitochondrial function, though both compounds disrupted IR-induced interaction between PPARα and CyP-D. In conclusion, A-769662 or SfA prevents PPARα interaction with CyP-D, improving cardiac outcomes and increasing mitochondrial function, and simultaneous administration of the drugs does not provide synergistic effects. Giselle Barreto-Torres and Sabzali Javadov Copyright © 2016 Giselle Barreto-Torres and Sabzali Javadov. All rights reserved. Inducible Conditional Vascular-Specific Overexpression of Peroxisome Proliferator-Activated Receptor Beta/Delta Leads to Rapid Cardiac Hypertrophy Thu, 03 Mar 2016 11:48:03 +0000 http://www.hindawi.com/journals/ppar/2016/7631085/ Peroxisome proliferator-activated receptors are nuclear receptors which function as ligand-activated transcription factors. Among them, peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) is highly expressed in the heart and thought to have cardioprotective functions due to its beneficial effects in metabolic syndrome. As we already showed that PPARβ/δ activation resulted in an enhanced cardiac angiogenesis and growth without impairment of heart function, we were interested to determine the effects of a specific activation of PPARβ/δ in the vasculature on cardiac performance under normal and in chronic ischemic heart disease conditions. We analyzed the effects of a specific PPARβ/δ overexpression in endothelial cells on the heart using an inducible conditional vascular-specific mouse model. We demonstrate that vessel-specific overexpression of PPARβ/δ induces rapid cardiac angiogenesis and growth with an increase in cardiomyocyte size. Upon myocardial infarction, vascular overexpression of PPARβ/δ, despite the enhanced cardiac vessel formation, does not protect against chronic ischemic injury. Our results suggest that the proper balance of PPARβ/δ activation in the different cardiac cell types is required to obtain beneficial effects on the outcome in chronic ischemic heart disease. Kay-Dietrich Wagner, Ana Vukolic, Delphine Baudouy, Jean-François Michiels, and Nicole Wagner Copyright © 2016 Kay-Dietrich Wagner et al. All rights reserved. PPARα Agonist Fenofibrate Reduced the Secreting Load of β-Cells in Hypertriglyceridemia Patients with Normal Glucose Tolerance Mon, 29 Feb 2016 08:00:35 +0000 http://www.hindawi.com/journals/ppar/2016/6232036/ Hypertriglyceridemia is an important risk factor associated with insulin resistance and β-cell dysfunction. This study investigated the effects of hypertriglyceridemia and fenofibrate treatment on insulin sensitivity and β-cell function in subjects with normal glucose tolerance. A total of 1974 subjects with normal glucose tolerance were divided into the normal TG group (NTG group, ) and hypertriglyceridemia group (HTG group, ). Next, 92 patients selected randomly from 672 patients with hypertriglyceridemia were assigned to a 24-week fenofibrate treatment. The HTG group had increased waist circumference (WC), body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of β-cell function (HOMA-β) and decreased high-density lipoprotein cholesterol (HDL-C) compared with the NTG group (all ). The 24-week fenofibrate treatment significantly decreased the WC, BMI, TG, HOMA-IR, and HOMA-β levels and increased the HDL-C levels in the patients with hypertriglyceridemia (WC, BMI, and HOMA-IR: ; TG, HDL-C, and HOMA-β: ). The fenofibrate treatment significantly alleviated insulin resistance and reduced the secreting load of β-cells in the hypertriglyceridemia patients with normal glucose tolerance. Jia Liu, Rui Lu, Ying Wang, Yanjin Hu, Yumei Jia, Ning Yang, Jing Fu, and Guang Wang Copyright © 2016 Jia Liu et al. All rights reserved. Differential Roles of Peroxisome Proliferator-Activated Receptor-α and Receptor-γ on Renal Crystal Formation in Hyperoxaluric Rodents Sun, 28 Feb 2016 11:32:04 +0000 http://www.hindawi.com/journals/ppar/2016/9605890/ Peroxisome proliferator-activated receptors (PPARs) and related inflammatory and oxidative molecule expression were investigated in a hyperoxaluric rodent model to evaluate the in vivo efficacy of PPAR agonists in preventing renal crystal formation. PPAR expression was examined in a mouse hyperoxaluria kidney stone model induced by daily intra-abdominal glyoxylate injection. Therapeutic effects of the PPARα agonist fenofibrate and PPARγ agonist pioglitazone were also assessed in a 1% ethylene glycol-induced rat model of hyperoxaluria. Crystal formation, inflammation, cell injury, apoptosis, and oxidative stress were compared to those of vehicle-treated controls. Quantitative reverse transcription-polymerase chain reaction revealed that PPARα and PPARγ expression decrease and increase, respectively, during crystal formation in hyperoxaluric kidneys. In addition, PPARα localized to the cytoplasm of both proximal and distal tubular cells, whereas PPARγ accumulated in the nucleus of proximal tubular cells. Furthermore, renal crystal formation was significantly less prevalent in pioglitazone-treated rats but higher in the fenofibrate-treated and fenofibrate/pioglitazone-cotreated groups compared to controls, thus indicating that pioglitazone, but not fenofibrate, markedly decreased cell inflammation, oxidative stress, and apoptosis. Collectively, the results demonstrated that PPARγ suppressed renal crystal formation via its antioxidative and anti-inflammatory effects; however, the renotoxicity of PPARα may elicit the opposite effect. Kazumi Taguchi, Atsushi Okada, Shuzo Hamamoto, Rei Unno, Takahiro Kobayashi, Ryosuke Ando, Keiichi Tozawa, Bing Gao, Kenjiro Kohri, and Takahiro Yasui Copyright © 2016 Kazumi Taguchi et al. All rights reserved. The Correlation of PPARα Activity and Cardiomyocyte Metabolism and Structure in Idiopathic Dilated Cardiomyopathy during Heart Failure Progression Mon, 15 Feb 2016 12:14:31 +0000 http://www.hindawi.com/journals/ppar/2016/7508026/ This study aimed to define relationship between PPAR expression and metabolic-structural characteristics during HF progression in hearts with DCM phenotype. Tissue endomyocardial biopsy samples divided into three groups according to LVEF ((I) 45–50%, ; (II) 30–40%, ; (III) <30%, ; and control (donor hearts, >60%, )) were investigated. The PPAR mRNA expression in the failing hearts was low in Group (I), high in Group (II), and comparable to that of the control in Group (III). There were analogous changes in the expression of FAT/CD36 and CPT-1 mRNA in contrast to continuous overexpression of GLUT-4 mRNA and significant increase of PDK-4 mRNA in Group (II). In addition, significant structural changes of cardiomyocytes with glycogen accumulation were accompanied by increased expression of PPAR. For the entire study population with HF levels of FAT/CD36 mRNA showed a strong tendency of negative correlation with LVEF. In conclusion, PPAR elevated levels may be a direct cause of adverse remodeling, both metabolic and structural. Thus, there is limited time window for therapy modulating cardiac metabolism and protecting cardiomyocyte structure in failing heart. E. Czarnowska, D. Domal-Kwiatkowska, E. Reichman-Warmusz, J. B. Bierla, A. Sowinska, A. Ratajska, K. Goral-Radziszewska, and R. Wojnicz Copyright © 2016 E. Czarnowska et al. All rights reserved. Polymorphisms of the PPAR-γ (rs1801282) and Its Coactivator (rs8192673) Have a Minor Effect on Markers of Carotid Atherosclerosis in Patients with Type 2 Diabetes Mellitus Tue, 02 Feb 2016 08:40:02 +0000 http://www.hindawi.com/journals/ppar/2016/4934251/ Background. The present study was designed to clarify whether common single nucleotide polymorphisms (SNPs) of the Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) gene (rs1801282) and the Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 (PGC-1α) gene (rs8192673) are associated with markers of carotid and coronary atherosclerosis in Caucasians with type 2 diabetes mellitus (T2DM). Patients and Methods. 595 T2DM subjects and 200 control subjects were enrolled in the cross-sectional study. Markers of carotid atherosclerosis were assessed ultrasonographically. In 215 out of 595 subjects with T2DM, a coronary computed tomography angiography (CCTA) was performed for diagnostic purposes. Genotyping of either rs1801282 or rs8192673 was performed using KASPar assays. Results. In our study, we demonstrated an effect of the rs1801282 on markers of carotid atherosclerosis (presence of plaques) in Caucasians with T2DM in univariate and in multivariable linear regression analyses. Finally, we did not demonstrate any association between either rs1801282 or rs8192673 and markers of coronary atherosclerosis. Conclusions. In our study, we demonstrated a minor effect of the rs1801282 on markers of carotid atherosclerosis (presence of plaques) in Caucasians with T2DM. Moreover, we demonstrated a minor effect of the rs8192673 on CIMT progression in the 3.8-year follow-up in Caucasians with T2DM. Aleš Pleskovič, Marija Šantl Letonja, Andreja Cokan Vujkovac, Jovana Nikolajević Starćević, and Danijel Petrovič Copyright © 2016 Aleš Pleskovič et al. All rights reserved. Caffeic Acid Phenethyl Ester Regulates PPAR’s Levels in Stem Cells-Derived Adipocytes Sun, 24 Jan 2016 09:19:14 +0000 http://www.hindawi.com/journals/ppar/2016/7359521/ Hypertrophic obesity inhibits activation of peroxisome proliferators-activated receptor gamma (PPARγ), considered the key mediator of the fully differentiated and insulin sensitive adipocyte phenotype. We examined the effects of Caffeic Acid Phenethyl Ester (Cape), isolated from propolis, a honeybee hive product, on Adipose Stem Cells (ASCs) differentiation to the adipocyte lineage. Finally we tested the effects of Cape on insulin-resistant adipocytes. Quantification of Oil Red O-stained cells showed that lipid droplets decreased following Cape treatment as well as radical oxygen species formation. Additionally, exposure of ASC to high glucose levels decreased adiponectin and increased proinflammatory cytokines mRNA levels, which were reversed by Cape-mediated increase of insulin sensitivity. Cape treatment resulted in decreased triglycerides synthesis and increased beta-oxidation. Exposure of ASCs to Lipopolysaccharide (LPS) induced a reduction of PPARγ, an increase of IL-6 levels associated with a well-known stimulation of lipolysis; Cape partially attenuated the LPS-mediated effects. These observations reveal the main role of PPARγ in the adipocyte function and during ASC differentiation. As there is now substantial interest in functional food and nutraceutical products, the observed therapeutic value of Cape in insulin-resistance related diseases should be taken into consideration. Luca Vanella, Daniele Tibullo, Justyna Godos, Francesca Romana Pluchinotta, Claudia Di Giacomo, Valeria Sorrenti, Rosaria Acquaviva, Alessandra Russo, Giovanni Li Volti, and Ignazio Barbagallo Copyright © 2016 Luca Vanella et al. All rights reserved.