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PPARs in Cellular and Whole Body Energy Metabolism

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 August 2018) | Viewed by 263642

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1. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
2. Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland
Interests: nuclear receptor superfamily; gene regulation and gene expression profiling; metabolic regulations; development; skin and wound healing; cancer; liver physiology; non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); adipose tissue; muscle and exercise; gut; microbiota; inter-organ cross-talk; nutrition; nutrigenetics and nutrigenomics
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Lee Kong Chian School of Medicine, Nanyang Technological University, Clinical Sciences Building,11 Mandalay Road, Singapore 308232, Singapore
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

All three peroxisome proliferator-activated receptor (PPAR) isotypes α, β/δ and γ, function as sensors for fatty acids and fatty acid derivatives, and control important metabolic pathways regulating cellular and whole body energy homeostasis. These ligand-dependent transcription factors, which belong to the nuclear receptor superfamily of transcription factors, have been targeted to fight metabolic diseases based on their metabolic regulatory activities in various tissues, in part depending on ligand selectivity. In fact, PPARs act as modulators of cellular, organ, and systemic processes, including lipid and carbohydrate metabolism, making them valuable for maintaining body homeostasis, particularly under the influence of nutrition and exercise. Each organ has a unique metabolic arrangement. For instance, the metabolic patterns of the liver, muscle, brain, adipose tissue, and kidney, are markedly different and these organs strikingly differ in their use of fuels to meet their energy needs. Furthermore, tumours also have their own metabolic processes that differ from those of noncancerous cells. Lastly, the energy substrates have also specific characteristics that require adaptive strategies. This Special Issue of IJMS will cover the singular and intricate regulatory roles of all three PPAR isotypes in the ensemble of processes that are associated with metabolism in the healthy and diseased organism.

Prof. Walter Wahli
Ms. Rachel Tee
Guest Editors

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Keywords

  • Peroxisome Proliferator-Activated Receptors (PPARs)

  • Energy homeostasis

  • Metabolic regulations

  • Organ cross-talk

  • Lipids and carbohydrates

  • Metabolic diseases

  • Cancer and reprogramming of energy metabolism

  • Systems biology

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Published Papers (32 papers)

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Research

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18 pages, 3890 KiB  
Article
Identification of a Novel PPAR-γ Agonist through a Scaffold Tuning Approach
by Hyo Jin Gim, Yong-Sung Choi, Hua Li, Yoon-Jung Kim, Jae-Ha Ryu and Raok Jeon
Int. J. Mol. Sci. 2018, 19(10), 3032; https://doi.org/10.3390/ijms19103032 - 4 Oct 2018
Cited by 14 | Viewed by 4284
Abstract
Peroxisome proliferator-activated receptors (PPARs) are important targets in metabolic diseases including obesity, metabolic syndrome, diabetes, and non-alcoholic fatty liver disease. Recently, they have been highlighted as attractive targets for the treatment of cardiovascular diseases and chronic myeloid leukemia. The PPAR agonist structure is [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) are important targets in metabolic diseases including obesity, metabolic syndrome, diabetes, and non-alcoholic fatty liver disease. Recently, they have been highlighted as attractive targets for the treatment of cardiovascular diseases and chronic myeloid leukemia. The PPAR agonist structure is consists of a polar head, a hydrophobic tail, and a linker. Each part interacts with PPARs through hydrogen bonds or hydrophobic interactions to stabilize target protein conformation, thus increasing its activity. Acidic head is essential for PPAR agonist activity. The aromatic linker plays an important role in making hydrophobic interactions with PPAR as well as adjusting the head-to-tail distance and conformation of the whole molecule. By tuning the scaffold of compound, the whole molecule could fit into the ligand-binding domain to achieve proper binding mode. We modified indol-3-ylacetic acid scaffold to (indol-1-ylmethyl)benzoic acid, whereas 2,4-dichloroanilide was fixed as the hydrophobic tail. We designed, synthesized, and assayed the in vitro activity of novel indole compounds with (indol-1-ylmethyl)benzoic acid scaffold. Compound 12 was a more potent PPAR-γ agonist than pioglitazone and our previous hit compound. Molecular docking studies may suggest the binding between compound 12 and PPAR-γ, rationalizing its high activity. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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12 pages, 3080 KiB  
Article
The Role of PPARβ/δ in Melanoma Metastasis
by Jonathan Chee Woei Lim, Yuet Ping Kwan, Michelle Siying Tan, Melissa Hui Yen Teo, Shunsuke Chiba, Walter Wahli and Xiaomeng Wang
Int. J. Mol. Sci. 2018, 19(10), 2860; https://doi.org/10.3390/ijms19102860 - 20 Sep 2018
Cited by 17 | Viewed by 5224
Abstract
Background: Peroxisome proliferator–activated receptor (PPAR) β/δ, a ligand-activated transcription factor, is involved in diverse biological processes including cell proliferation, cell differentiation, inflammation and energy homeostasis. Besides its well-established roles in metabolic disorders, PPARβ/δ has been linked to carcinogenesis and was reported to inhibit [...] Read more.
Background: Peroxisome proliferator–activated receptor (PPAR) β/δ, a ligand-activated transcription factor, is involved in diverse biological processes including cell proliferation, cell differentiation, inflammation and energy homeostasis. Besides its well-established roles in metabolic disorders, PPARβ/δ has been linked to carcinogenesis and was reported to inhibit melanoma cell proliferation, anchorage-dependent clonogenicity and ectopic xenograft tumorigenicity. However, PPARβ/δ’s role in tumour progression and metastasis remains controversial. Methods: In the present studies, the consequence of PPARβ/δ inhibition either by global genetic deletion or by a specific PPARβ/δ antagonist, 10h, on malignant transformation of melanoma cells and melanoma metastasis was examined using both in vitro and in vivo models. Results: Our study showed that 10h promotes epithelial-mesenchymal transition (EMT), migration, adhesion, invasion and trans-endothelial migration of mouse melanoma B16/F10 cells. We further demonstrated an increased tumour cell extravasation in the lungs of wild-type mice subjected to 10h treatment and in Pparβ/δ−/− mice in an experimental mouse model of blood-borne pulmonary metastasis by tail vein injection. This observation was further supported by an increased tumour burden in the lungs of Pparβ/δ−/− mice as demonstrated in the same animal model. Conclusion: These results indicated a protective role of PPARβ/δ in melanoma progression and metastasis. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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17 pages, 2474 KiB  
Article
PPARγ Controls Ectopic Adipogenesis and Cross-Talks with Myogenesis During Skeletal Muscle Regeneration
by Gabriele Dammone, Sonia Karaz, Laura Lukjanenko, Carine Winkler, Federico Sizzano, Guillaume Jacot, Eugenia Migliavacca, Alessio Palini, Béatrice Desvergne, Federica Gilardi and Jerome N. Feige
Int. J. Mol. Sci. 2018, 19(7), 2044; https://doi.org/10.3390/ijms19072044 - 13 Jul 2018
Cited by 36 | Viewed by 5994
Abstract
Skeletal muscle is a regenerative tissue which can repair damaged myofibers through the activation of tissue-resident muscle stem cells (MuSCs). Many muscle diseases with impaired regeneration cause excessive adipose tissue accumulation in muscle, alter the myogenic fate of MuSCs, and deregulate the cross-talk [...] Read more.
Skeletal muscle is a regenerative tissue which can repair damaged myofibers through the activation of tissue-resident muscle stem cells (MuSCs). Many muscle diseases with impaired regeneration cause excessive adipose tissue accumulation in muscle, alter the myogenic fate of MuSCs, and deregulate the cross-talk between MuSCs and fibro/adipogenic progenitors (FAPs), a bi-potent cell population which supports myogenesis and controls intra-muscular fibrosis and adipocyte formation. In order to better characterize the interaction between adipogenesis and myogenesis, we studied muscle regeneration and MuSC function in whole body Pparg null mice generated by epiblast-specific Cre/lox deletion (PpargΔ/Δ). We demonstrate that deletion of PPARγ completely abolishes ectopic muscle adipogenesis during regeneration and impairs MuSC expansion and myogenesis after injury. Ex vivo assays revealed that perturbed myogenesis in PpargΔ/Δ mice does not primarily result from intrinsic defects of MuSCs or from perturbed myogenic support from FAPs. The immune transition from a pro- to anti-inflammatory MuSC niche during regeneration is perturbed in PpargΔ/Δ mice and suggests that PPARγ signaling in macrophages can interact with ectopic adipogenesis and influence muscle regeneration. Altogether, our study demonstrates that a PPARγ-dependent adipogenic response regulates muscle fat infiltration during regeneration and that PPARγ is required for MuSC function and efficient muscle repair. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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9 pages, 1809 KiB  
Article
The Contribution of EDF1 to PPARγ Transcriptional Activation in VEGF-Treated Human Endothelial Cells
by Alessandra Cazzaniga, Laura Locatelli, Sara Castiglioni and Jeanette Maier
Int. J. Mol. Sci. 2018, 19(7), 1830; https://doi.org/10.3390/ijms19071830 - 21 Jun 2018
Cited by 10 | Viewed by 4300
Abstract
Vascular endothelial growth factor (VEGF) is important for maintaining healthy endothelium, which is crucial for vascular integrity. In this paper, we show that VEGF stimulates the nuclear translocation of endothelial differentiation-related factor 1 (EDF1), a highly conserved intracellular protein implicated in molecular events [...] Read more.
Vascular endothelial growth factor (VEGF) is important for maintaining healthy endothelium, which is crucial for vascular integrity. In this paper, we show that VEGF stimulates the nuclear translocation of endothelial differentiation-related factor 1 (EDF1), a highly conserved intracellular protein implicated in molecular events that are pivotal to endothelial function. In the nucleus, EDF1 serves as a transcriptional coactivator of peroxisome proliferator-activated receptor gamma (PPARγ), which has a protective role in the vasculature. Indeed, silencing EDF1 prevents VEGF induction of PPARγ activity as detected by gene reporter assay. Accordingly, silencing EDF1 markedly inhibits the stimulatory effect of VEGF on the expression of FABP4, a PPARγ-inducible gene. As nitric oxide is a marker of endothelial function, it is noteworthy that we report a link between EDF1 silencing, decreased levels of FABP4, and nitric oxide production. We conclude that EDF1 is required for VEGF-induced activation of the transcriptional activity of PPARγ. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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18 pages, 1955 KiB  
Article
PIMT/NCOA6IP Deletion in the Mouse Heart Causes Delayed Cardiomyopathy Attributable to Perturbation in Energy Metabolism
by Yuzhi Jia, Ning Liu, Navin Viswakarma, Ruya Sun, Mathew J. Schipma, Meng Shang, Edward B. Thorp, Yashpal S. Kanwar, Bayar Thimmapaya and Janardan K. Reddy
Int. J. Mol. Sci. 2018, 19(5), 1485; https://doi.org/10.3390/ijms19051485 - 16 May 2018
Cited by 8 | Viewed by 5826
Abstract
PIMT/NCOA6IP, a transcriptional coactivator PRIP/NCOA6 binding protein, enhances nuclear receptor transcriptional activity. Germline disruption of PIMT results in early embryonic lethality due to impairment of development around blastocyst and uterine implantation stages. We now generated mice with Cre-mediated cardiac-specific deletion of PIMT (csPIMT [...] Read more.
PIMT/NCOA6IP, a transcriptional coactivator PRIP/NCOA6 binding protein, enhances nuclear receptor transcriptional activity. Germline disruption of PIMT results in early embryonic lethality due to impairment of development around blastocyst and uterine implantation stages. We now generated mice with Cre-mediated cardiac-specific deletion of PIMT (csPIMT−/−) in adult mice. These mice manifest enlargement of heart, with nearly 100% mortality by 7.5 months of age due to dilated cardiomyopathy. Significant reductions in the expression of genes (i) pertaining to mitochondrial respiratory chain complexes I to IV; (ii) calcium cycling cardiac muscle contraction (Atp2a1, Atp2a2, Ryr2); and (iii) nuclear receptor PPAR- regulated genes involved in glucose and fatty acid energy metabolism were found in csPIMT−/− mouse heart. Elevated levels of Nppa and Nppb mRNAs were noted in csPIMT−/− heart indicative of myocardial damage. These hearts revealed increased reparative fibrosis associated with enhanced expression of Tgfβ2 and Ctgf. Furthermore, cardiac-specific deletion of PIMT in adult mice, using tamoxifen-inducible Cre-approach (TmcsPIMT−/−), results in the development of cardiomyopathy. Thus, cumulative evidence suggests that PIMT functions in cardiac energy metabolism by interacting with nuclear receptor coactivators and this property could be useful in the management of heart failure. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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11 pages, 234 KiB  
Article
Influence of Single-Nucleotide Polymorphisms in PPAR-δ, PPAR-γ, and PRKAA2 on the Changes in Anthropometric Indices and Blood Measurements through Exercise-Centered Lifestyle Intervention in Japanese Middle-Aged Men
by Yuichiro Nishida, Minako Iyadomi, Hirotaka Tominaga, Hiroaki Taniguchi, Yasuki Higaki, Hiroaki Tanaka, Mikako Horita, Chisato Shimanoe, Megumi Hara and Keitaro Tanaka
Int. J. Mol. Sci. 2018, 19(3), 703; https://doi.org/10.3390/ijms19030703 - 1 Mar 2018
Cited by 6 | Viewed by 3693
Abstract
The purpose of the current study was to examine the influence of single-nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-δ (PPAR-δ), PPAR-γ, and α2 isoforms of the catalytic subunit of AMP-activated protein kinase (PRKAA2) on the extent of changes in anthropometric indices and [...] Read more.
The purpose of the current study was to examine the influence of single-nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-δ (PPAR-δ), PPAR-γ, and α2 isoforms of the catalytic subunit of AMP-activated protein kinase (PRKAA2) on the extent of changes in anthropometric indices and blood measurements through exercise-centered lifestyle intervention in middle-aged men. A total of 109 Japanese middle-aged male subjects (47.0 ± 0.4 years) participated in the baseline health checkup, 6-month exercise-centered lifestyle intervention, and second checkup conducted several months after the subject completed the intervention. The body mass index (BMI), waist circumference, and clinical measurements, including hemoglobin Alc (HbA1c), triglyceride (TG), alanine aminotransferase (ALT), and γ-glutamyl-transpeptidase (γ-GTP), were measured at the baseline and second checkup. The three SNPs of PPAR-δ A/G (rs2267668), PPAR-γ C/G (rs1801282), and PRKAA2 A/G (rs1418442) were determined. Blunted responses in the reduction in the BMI and waist circumference were observed in A/A carriers of PPAR-δ SNP compared with G allele carriers (all p < 0.05). The A/A carriers also displayed less-marked improvements in HbA1c, TG, ALT, and γ-GTP (all p < 0.05). The current results suggest that A/A carriers of PPAR-δ SNP (rs2267668) may enjoy fewer beneficial effects of exercise-centered lifestyle intervention on anthropometric indices and blood measurements. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
15 pages, 2406 KiB  
Article
Molecular Modeling Study for the Design of Novel Peroxisome Proliferator-Activated Receptor Gamma Agonists Using 3D-QSAR and Molecular Docking
by Yaning Jian, Yuyu He, Jingjing Yang, Wei Han, Xifeng Zhai, Ye Zhao and Yang Li
Int. J. Mol. Sci. 2018, 19(2), 630; https://doi.org/10.3390/ijms19020630 - 23 Feb 2018
Cited by 13 | Viewed by 5190
Abstract
Type 2 diabetes is becoming a global pandemic disease. As an important target for the generation and development of diabetes mellitus, peroxisome proliferator-activated receptor γ (PPARγ) has been widely studied. PPARγ agonists have been designed as potential anti-diabetic agents. The advanced development of [...] Read more.
Type 2 diabetes is becoming a global pandemic disease. As an important target for the generation and development of diabetes mellitus, peroxisome proliferator-activated receptor γ (PPARγ) has been widely studied. PPARγ agonists have been designed as potential anti-diabetic agents. The advanced development of PPARγ agonists represents a valuable research tool for diabetes therapy. To explore the structural requirements of PPARγ agonists, three-dimensional quantitative structure–activity relationship (3D-QSAR) and molecular docking studies were performed on a series of N-benzylbenzamide derivatives employing comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and surflex-dock techniques. The generated models of CoMFA and CoMSIA exhibited a high cross-validation coefficient (q2) of 0.75 and 0.551, and a non-cross-validation coefficient (r2) of 0.958 and 0.912, respectively. The predictive ability of the models was validated using external validation with predictive factor (r2pred) of 0.722 and 0.682, respectively. These results indicate that the model has high statistical reliability and good predictive power. The probable binding modes of the best active compounds with PPARγ active site were analyzed, and the residues His323, Tyr473, Ser289 and Ser342 were found to have hydrogen bond interactions. Based on the analysis of molecular docking results, and the 3D contour maps generated from CoMFA and CoMSIA models, the key structural features of PPARγ agonists responsible for biological activity could be determined, and several new molecules, with potentially higher predicted activity, were designed thereafter. This work may provide valuable information in further optimization of N-benzylbenzamide derivatives as PPARγ agonists. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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1144 KiB  
Article
Activation of PPARα by Oral Clofibrate Increases Renal Fatty Acid Oxidation in Developing Pigs
by Yonghui He, Imad Khan, Xiumei Bai, Jack Odle and Lin Xi
Int. J. Mol. Sci. 2017, 18(12), 2663; https://doi.org/10.3390/ijms18122663 - 8 Dec 2017
Cited by 9 | Viewed by 4033
Abstract
The objective of this study was to evaluate the effects of peroxisome proliferator-activated receptor α (PPARα) activation by clofibrate on both mitochondrial and peroxisomal fatty acid oxidation in the developing kidney. Ten newborn pigs from 5 litters were randomly assigned to two groups [...] Read more.
The objective of this study was to evaluate the effects of peroxisome proliferator-activated receptor α (PPARα) activation by clofibrate on both mitochondrial and peroxisomal fatty acid oxidation in the developing kidney. Ten newborn pigs from 5 litters were randomly assigned to two groups and fed either 5 mL of a control vehicle (2% Tween 80) or a vehicle containing clofibrate (75 mg/kg body weight, treatment). The pigs received oral gavage daily for three days. In vitro fatty acid oxidation was then measured in kidneys with and without mitochondria inhibitors (antimycin A and rotenone) using [1-14C]-labeled oleic acid (C18:1) and erucic acid (C22:1) as substrates. Clofibrate significantly stimulated C18:1 and C22:1 oxidation in mitochondria (p < 0.001) but not in peroxisomes. In addition, the oxidation rate of C18:1 was greater in mitochondria than peroxisomes, while the oxidation of C22:1 was higher in peroxisomes than mitochondria (p < 0.001). Consistent with the increase in fatty acid oxidation, the mRNA abundance and enzyme activity of carnitine palmitoyltransferase I (CPT I) in mitochondria were increased. Although mRNA of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (mHMGCS) was increased, the β-hydroxybutyrate concentration measured in kidneys did not increase in pigs treated with clofibrate. These findings indicate that PPARα activation stimulates renal fatty acid oxidation but not ketogenesis. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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3336 KiB  
Article
PPARγ Modulates Long Chain Fatty Acid Processing in the Intestinal Epithelium
by Kalina Duszka, Matej Oresic, Cedric Le May, Jürgen König and Walter Wahli
Int. J. Mol. Sci. 2017, 18(12), 2559; https://doi.org/10.3390/ijms18122559 - 28 Nov 2017
Cited by 43 | Viewed by 6144
Abstract
Nuclear receptor PPARγ affects lipid metabolism in several tissues, but its role in intestinal lipid metabolism has not been explored. As alterations have been observed in the plasma lipid profile of ad libitum fed intestinal epithelium-specific PPARγ knockout mice (iePPARγKO), we submitted these [...] Read more.
Nuclear receptor PPARγ affects lipid metabolism in several tissues, but its role in intestinal lipid metabolism has not been explored. As alterations have been observed in the plasma lipid profile of ad libitum fed intestinal epithelium-specific PPARγ knockout mice (iePPARγKO), we submitted these mice to lipid gavage challenges. Within hours after gavage with long chain unsaturated fatty acid (FA)-rich canola oil, the iePPARγKO mice had higher plasma free FA levels and lower gastric inhibitory polypeptide levels than their wild-type (WT) littermates, and altered expression of incretin genes and lipid metabolism-associated genes in the intestinal epithelium. Gavage with the medium chain saturated FA-rich coconut oil did not result in differences between the two genotypes. Furthermore, the iePPARγKO mice did not exhibit defective lipid uptake and stomach emptying; however, their intestinal transit was more rapid than in WT mice. When fed a canola oil-rich diet for 4.5 months, iePPARγKO mice had higher body lean mass than the WT mice. We conclude that intestinal epithelium PPARγ is activated preferentially by long chain unsaturated FAs compared to medium chain saturated FAs. Furthermore, we hypothesize that the iePPARγKO phenotype originates from altered lipid metabolism and release in epithelial cells, as well as changes in intestinal motility. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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Review

Jump to: Research

24 pages, 2457 KiB  
Review
Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue
by Daniel Heudobler, Michael Rechenmacher, Florian Lüke, Martin Vogelhuber, Tobias Pukrop, Wolfgang Herr, Lina Ghibelli, Christopher Gerner and Albrecht Reichle
Int. J. Mol. Sci. 2018, 19(11), 3540; https://doi.org/10.3390/ijms19113540 - 9 Nov 2018
Cited by 44 | Viewed by 5178
Abstract
In most clinical trials, thiazolidinediones do not show any relevant anti-cancer activity when used as mono-therapy. Clinical inefficacy contrasts ambiguous pre-clinical data either favoring anti-tumor activity or tumor promotion. However, if thiazolidinediones are combined with additional regulatory active drugs, so-called ‘master modulators’ of [...] Read more.
In most clinical trials, thiazolidinediones do not show any relevant anti-cancer activity when used as mono-therapy. Clinical inefficacy contrasts ambiguous pre-clinical data either favoring anti-tumor activity or tumor promotion. However, if thiazolidinediones are combined with additional regulatory active drugs, so-called ‘master modulators’ of tumors, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs, etc., the results indicate clinically relevant communicative reprogramming of tumor tissues, i.e., anakoinosis, meaning ‘communication’ in ancient Greek. The concerted activity of master modulators may multifaceted diversify palliative care or even induce continuous complete remission in refractory metastatic tumor disease and hematologic neoplasia by establishing novel communicative behavior of tumor tissue, the hosting organ, and organism. Re-modulation of gene expression, for example, the up-regulation of tumor suppressor genes, may recover differentiation, apoptosis competence, and leads to cancer control—in contrast to an immediate, ‘poisoning’ with maximal tolerable doses of targeted/cytotoxic therapies. The key for uncovering the therapeutic potential of Peroxisome proliferator-activated receptor γ (PPARγ) agonists is selecting the appropriate combination of master modulators for inducing anakoinosis: Now, anakoinosis is trend setting by establishing a novel therapeutic pillar while overcoming classic obstacles of targeted therapies, such as therapy resistance and (molecular-)genetic tumor heterogeneity. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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17 pages, 2023 KiB  
Review
Elucidating the Beneficial Role of PPAR Agonists in Cardiac Diseases
by Zaza Khuchua, Aleksandr I. Glukhov, Arnold W. Strauss and Sabzali Javadov
Int. J. Mol. Sci. 2018, 19(11), 3464; https://doi.org/10.3390/ijms19113464 - 4 Nov 2018
Cited by 45 | Viewed by 5975
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that bind to DNA and regulate transcription of genes involved in lipid and glucose metabolism. A growing number of studies provide strong evidence that PPARs are the promising pharmacological targets for therapeutic intervention in various [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that bind to DNA and regulate transcription of genes involved in lipid and glucose metabolism. A growing number of studies provide strong evidence that PPARs are the promising pharmacological targets for therapeutic intervention in various diseases including cardiovascular disorders caused by compromised energy metabolism. PPAR agonists have been widely used for decades as lipid-lowering and anti-inflammatory drugs. Existing studies are mainly focused on the anti-atherosclerotic effects of PPAR agonists; however, their role in the maintenance of cellular bioenergetics remains unclear. Recent studies on animal models and patients suggest that PPAR agonists can normalize lipid metabolism by stimulating fatty acid oxidation. These studies indicate the importance of elucidation of PPAR agonists as potential pharmacological agents for protection of the heart from energy deprivation. Here, we summarize and provide a comprehensive analysis of previous studies on the role of PPARs in the heart under normal and pathological conditions. In addition, the review discusses the PPARs as a therapeutic target and the beneficial effects of PPAR agonists, particularly bezafibrate, to attenuate cardiomyopathy and heart failure in patients and animal models. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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21 pages, 1463 KiB  
Review
PGC-1α as a Pivotal Factor in Lipid and Metabolic Regulation
by Ching-Feng Cheng, Hui-Chen Ku and Heng Lin
Int. J. Mol. Sci. 2018, 19(11), 3447; https://doi.org/10.3390/ijms19113447 - 2 Nov 2018
Cited by 263 | Viewed by 24651
Abstract
Traditionally, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a 91 kDa transcription factor, regulates lipid metabolism and long-chain fatty acid oxidation by upregulating the expression of several genes of the tricarboxylic acid cycle and the mitochondrial fatty acid oxidation pathway. In addition, PGC-1α [...] Read more.
Traditionally, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a 91 kDa transcription factor, regulates lipid metabolism and long-chain fatty acid oxidation by upregulating the expression of several genes of the tricarboxylic acid cycle and the mitochondrial fatty acid oxidation pathway. In addition, PGC-1α regulates the expression of mitochondrial genes to control mitochondria DNA replication and cellular oxidative metabolism. Recently, new insights showed that several myokines such as irisin and myostatin are epigenetically regulated by PGC-1α in skeletal muscles, thereby modulating systemic energy balance, with marked expansion of mitochondrial volume density and oxidative capacity in healthy or diseased myocardia. In addition, in our studies evaluating whether PGC-1α overexpression in epicardial adipose tissue can act as a paracrine organ to improve or repair cardiac function, we found that overexpression of hepatic PGC-1α increased hepatic fatty acid oxidation and decreased triacylglycerol storage and secretion in vivo and in vitro. In this review, we discuss recent studies showing that PGC-1α may regulate mitochondrial fusion–fission homeostasis and affect the renal function in acute or chronic kidney injury. Furthermore, PGC-1α is an emerging protein with a biphasic role in cancer, acting both as a tumor suppressor and a tumor promoter and thus representing a new and unresolved topic for cancer biology studies. In summary, this review paper demonstrates that PGC-1α plays a central role in coordinating the gene expression of key components of mitochondrial biogenesis and as a critical metabolic regulator in many vital organs, including white and brown adipose tissue, skeletal muscle, heart, liver, and kidney. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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14 pages, 700 KiB  
Review
The Role of PPAR-δ in Metabolism, Inflammation, and Cancer: Many Characters of a Critical Transcription Factor
by Yi Liu, Jennifer K. Colby, Xiangsheng Zuo, Jonathan Jaoude, Daoyan Wei and Imad Shureiqi
Int. J. Mol. Sci. 2018, 19(11), 3339; https://doi.org/10.3390/ijms19113339 - 26 Oct 2018
Cited by 121 | Viewed by 14184
Abstract
Peroxisome proliferator-activated receptor-delta (PPAR-δ), one of three members of the PPAR group in the nuclear receptor superfamily, is a ligand-activated transcription factor. PPAR-δ regulates important cellular metabolic functions that contribute to maintaining energy balance. PPAR-δ is especially important in regulating fatty acid uptake, [...] Read more.
Peroxisome proliferator-activated receptor-delta (PPAR-δ), one of three members of the PPAR group in the nuclear receptor superfamily, is a ligand-activated transcription factor. PPAR-δ regulates important cellular metabolic functions that contribute to maintaining energy balance. PPAR-δ is especially important in regulating fatty acid uptake, transport, and β-oxidation as well as insulin secretion and sensitivity. These salutary PPAR-δ functions in normal cells are thought to protect against metabolic-syndrome-related diseases, such as obesity, dyslipidemia, insulin resistance/type 2 diabetes, hepatosteatosis, and atherosclerosis. Given the high clinical burden these diseases pose, highly selective synthetic activating ligands of PPAR-δ were developed as potential preventive/therapeutic agents. Some of these compounds showed some efficacy in clinical trials focused on metabolic-syndrome-related conditions. However, the clinical development of PPAR-δ agonists was halted because various lines of evidence demonstrated that cancer cells upregulated PPAR-δ expression/activity as a defense mechanism against nutritional deprivation and energy stresses, improving their survival and promoting cancer progression. This review discusses the complex relationship between PPAR-δ in health and disease and highlights our current knowledge regarding the different roles that PPAR-δ plays in metabolism, inflammation, and cancer. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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29 pages, 1223 KiB  
Review
The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development
by Fan Hong, Pengfei Xu and Yonggong Zhai
Int. J. Mol. Sci. 2018, 19(8), 2189; https://doi.org/10.3390/ijms19082189 - 27 Jul 2018
Cited by 104 | Viewed by 10667
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a well-known pharmacological target for the treatment of multiple diseases, including diabetes mellitus, dyslipidemia, cardiovascular diseases and even primary biliary cholangitis, gout, cancer, Alzheimer’s disease and ulcerative colitis. The three PPAR isoforms (α, β/δ and γ) have emerged [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) are a well-known pharmacological target for the treatment of multiple diseases, including diabetes mellitus, dyslipidemia, cardiovascular diseases and even primary biliary cholangitis, gout, cancer, Alzheimer’s disease and ulcerative colitis. The three PPAR isoforms (α, β/δ and γ) have emerged as integrators of glucose and lipid metabolic signaling networks. Typically, PPARα is activated by fibrates, which are commonly used therapeutic agents in the treatment of dyslipidemia. The pharmacological activators of PPARγ include thiazolidinediones (TZDs), which are insulin sensitizers used in the treatment of type 2 diabetes mellitus (T2DM), despite some drawbacks. In this review, we summarize 84 types of PPAR synthetic ligands introduced to date for the treatment of metabolic and other diseases and provide a comprehensive analysis of the current applications and problems of these ligands in clinical drug discovery and development. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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16 pages, 3597 KiB  
Review
PPARs and Metabolic Disorders Associated with Challenged Adipose Tissue Plasticity
by Patricia Corrales, Antonio Vidal-Puig and Gema Medina-Gómez
Int. J. Mol. Sci. 2018, 19(7), 2124; https://doi.org/10.3390/ijms19072124 - 21 Jul 2018
Cited by 119 | Viewed by 8566
Abstract
Peroxisome proliferator-activated receptors (PPARs) are members of a family of nuclear hormone receptors that exert their transcriptional control on genes harboring PPAR-responsive regulatory elements (PPRE) in partnership with retinoid X receptors (RXR). The activation of PPARs coordinated by specific coactivators/repressors regulate networks of [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) are members of a family of nuclear hormone receptors that exert their transcriptional control on genes harboring PPAR-responsive regulatory elements (PPRE) in partnership with retinoid X receptors (RXR). The activation of PPARs coordinated by specific coactivators/repressors regulate networks of genes controlling diverse homeostatic processes involving inflammation, adipogenesis, lipid metabolism, glucose homeostasis, and insulin resistance. Defects in PPARs have been linked to lipodystrophy, obesity, and insulin resistance as a result of the impairment of adipose tissue expandability and functionality. PPARs can act as lipid sensors, and when optimally activated, can rewire many of the metabolic pathways typically disrupted in obesity leading to an improvement of metabolic homeostasis. PPARs also contribute to the homeostasis of adipose tissue under challenging physiological circumstances, such as pregnancy and aging. Given their potential pathogenic role and their therapeutic potential, the benefits of PPARs activation should not only be considered relevant in the context of energy balance-associated pathologies and insulin resistance but also as potential relevant targets in the context of diabetic pregnancy and changes in body composition and metabolic stress associated with aging. Here, we review the rationale for the optimization of PPAR activation under these conditions. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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12 pages, 1301 KiB  
Review
Maintenance of Kidney Metabolic Homeostasis by PPAR Gamma
by Patricia Corrales, Adriana Izquierdo-Lahuerta and Gema Medina-Gómez
Int. J. Mol. Sci. 2018, 19(7), 2063; https://doi.org/10.3390/ijms19072063 - 16 Jul 2018
Cited by 55 | Viewed by 9004
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that control the transcription of specific genes by binding to regulatory DNA sequences. Among the three subtypes of PPARs, PPARγ modulates a broad range of physiopathological processes, including lipid metabolism, insulin sensitization, [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that control the transcription of specific genes by binding to regulatory DNA sequences. Among the three subtypes of PPARs, PPARγ modulates a broad range of physiopathological processes, including lipid metabolism, insulin sensitization, cellular differentiation, and cancer. Although predominantly expressed in adipose tissue, PPARγ expression is also found in different regions of the kidney and, upon activation, can redirect metabolism. Recent studies have highlighted important roles for PPARγ in kidney metabolism, such as lipid and glucose metabolism and renal mineral control. PPARγ is also implicated in the renin-angiotensin-aldosterone system and, consequently, in the control of systemic blood pressure. Accordingly, synthetic agonists of PPARγ have reno-protective effects both in diabetic and nondiabetic patients. This review focuses on the role of PPARγ in renal metabolism as a likely key factor in the maintenance of systemic homeostasis. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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23 pages, 602 KiB  
Review
PPARβ/δ: Linking Metabolism to Regeneration
by Ajit Magadum and Felix B. Engel
Int. J. Mol. Sci. 2018, 19(7), 2013; https://doi.org/10.3390/ijms19072013 - 10 Jul 2018
Cited by 66 | Viewed by 8384
Abstract
In contrast to the general belief that regeneration is a rare event, mainly occurring in simple organisms, the ability of regeneration is widely distributed in the animal kingdom. Yet, the efficiency and extent of regeneration varies greatly. Humans can recover from blood loss [...] Read more.
In contrast to the general belief that regeneration is a rare event, mainly occurring in simple organisms, the ability of regeneration is widely distributed in the animal kingdom. Yet, the efficiency and extent of regeneration varies greatly. Humans can recover from blood loss as well as damage to tissues like bone and liver. Yet damage to the heart and brain cannot be reversed, resulting in scaring. Thus, there is a great interest in understanding the molecular mechanisms of naturally occurring regeneration and to apply this knowledge to repair human organs. During regeneration, injury-activated immune cells induce wound healing, extracellular matrix remodeling, migration, dedifferentiation and/or proliferation with subsequent differentiation of somatic or stem cells. An anti-inflammatory response stops the regenerative process, which ends with tissue remodeling to achieve the original functional state. Notably, many of these processes are associated with enhanced glycolysis. Therefore, peroxisome proliferator-activated receptor (PPAR) β/δ—which is known to be involved for example in lipid catabolism, glucose homeostasis, inflammation, survival, proliferation, differentiation, as well as mammalian regeneration of the skin, bone and liver—appears to be a promising target to promote mammalian regeneration. This review summarizes our current knowledge of PPARβ/δ in processes associated with wound healing and regeneration. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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30 pages, 2014 KiB  
Review
The Involvement of PPARs in the Peculiar Energetic Metabolism of Tumor Cells
by Andrea Antonosante, Michele D’Angelo, Vanessa Castelli, Mariano Catanesi, Dalila Iannotta, Antonio Giordano, Rodolfo Ippoliti, Elisabetta Benedetti and Annamaria Cimini
Int. J. Mol. Sci. 2018, 19(7), 1907; https://doi.org/10.3390/ijms19071907 - 29 Jun 2018
Cited by 26 | Viewed by 5870
Abstract
Energy homeostasis is crucial for cell fate, since all cellular activities are strongly dependent on the balance between catabolic and anabolic pathways. In particular, the modulation of metabolic and energetic pathways in cancer cells has been discussed in some reports, but subsequently has [...] Read more.
Energy homeostasis is crucial for cell fate, since all cellular activities are strongly dependent on the balance between catabolic and anabolic pathways. In particular, the modulation of metabolic and energetic pathways in cancer cells has been discussed in some reports, but subsequently has been neglected for a long time. Meanwhile, over the past 20 years, a recovery of the study regarding cancer metabolism has led to an increasing consideration of metabolic alterations in tumors. Cancer cells must adapt their metabolism to meet their energetic and biosynthetic demands, which are associated with the rapid growth of the primary tumor and colonization of distinct metastatic sites. Cancer cells are largely dependent on aerobic glycolysis for their energy production, but are also associated with increased fatty acid synthesis and increased rates of glutamine consumption. In fact, emerging evidence has shown that therapeutic resistance to cancer treatment may arise from the deregulation of glucose metabolism, fatty acid synthesis, and glutamine consumption. Cancer cells exhibit a series of metabolic alterations induced by mutations that lead to a gain-of-function of oncogenes, and a loss-of-function of tumor suppressor genes, including increased glucose consumption, reduced mitochondrial respiration, an increase of reactive oxygen species, and cell death resistance; all of these are responsible for cancer progression. Cholesterol metabolism is also altered in cancer cells and supports uncontrolled cell growth. In this context, we discuss the roles of peroxisome proliferator-activated receptors (PPARs), which are master regulators of cellular energetic metabolism in the deregulation of the energetic homeostasis, which is observed in cancer. We highlight the different roles of PPAR isotypes and the differential control of their transcription in various cancer cells. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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23 pages, 1820 KiB  
Review
Insights into the Role of PPARβ/δ in NAFLD
by Jiapeng Chen, Alexandra Montagner, Nguan Soon Tan and Walter Wahli
Int. J. Mol. Sci. 2018, 19(7), 1893; https://doi.org/10.3390/ijms19071893 - 27 Jun 2018
Cited by 52 | Viewed by 7502
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health issue in developed countries. Although usually associated with obesity, NAFLD is also diagnosed in individuals with low body mass index (BMI) values, especially in Asia. NAFLD can progress from steatosis to non-alcoholic steatohepatitis (NASH), [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is a major health issue in developed countries. Although usually associated with obesity, NAFLD is also diagnosed in individuals with low body mass index (BMI) values, especially in Asia. NAFLD can progress from steatosis to non-alcoholic steatohepatitis (NASH), which is characterized by liver damage and inflammation, leading to cirrhosis and hepatocellular carcinoma (HCC). NAFLD development can be induced by lipid metabolism alterations; imbalances of pro- and anti-inflammatory molecules; and changes in various other factors, such as gut nutrient-derived signals and adipokines. Obesity-related metabolic disorders may be improved by activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)β/δ, which is involved in metabolic processes and other functions. This review is focused on research findings related to PPARβ/δ-mediated regulation of hepatic lipid and glucose metabolism and NAFLD development. It also discusses the potential use of pharmacological PPARβ/δ activation for NAFLD treatment. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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16 pages, 543 KiB  
Review
PPARs and Energy Metabolism Adaptation during Neurogenesis and Neuronal Maturation
by Michele D’Angelo, Andrea Antonosante, Vanessa Castelli, Mariano Catanesi, NandhaKumar Moorthy, Dalila Iannotta, Annamaria Cimini and Elisabetta Benedetti
Int. J. Mol. Sci. 2018, 19(7), 1869; https://doi.org/10.3390/ijms19071869 - 26 Jun 2018
Cited by 15 | Viewed by 5413
Abstract
Peroxisome proliferator activated receptors (PPARs) are a class of ligand-activated transcription factors, belonging to the superfamily of receptors for steroid and thyroid hormones, retinoids, and vitamin D. PPARs control the expression of several genes connected with carbohydrate and lipid metabolism, and it has [...] Read more.
Peroxisome proliferator activated receptors (PPARs) are a class of ligand-activated transcription factors, belonging to the superfamily of receptors for steroid and thyroid hormones, retinoids, and vitamin D. PPARs control the expression of several genes connected with carbohydrate and lipid metabolism, and it has been demonstrated that PPARs play important roles in determining neural stem cell (NSC) fate. Lipogenesis and aerobic glycolysis support the rapid proliferation during neurogenesis, and specific roles for PPARs in the control of different phases of neurogenesis have been demonstrated. Understanding the changes in metabolism during neuronal differentiation is important in the context of stem cell research, neurodegenerative diseases, and regenerative medicine. In this review, we will discuss pivotal evidence that supports the role of PPARs in energy metabolism alterations during neuronal maturation and neurodegenerative disorders. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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16 pages, 1167 KiB  
Review
Functional Regulation of PPARs through Post-Translational Modifications
by Reinhard Brunmeir and Feng Xu
Int. J. Mol. Sci. 2018, 19(6), 1738; https://doi.org/10.3390/ijms19061738 - 12 Jun 2018
Cited by 158 | Viewed by 11181
Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and they are essential regulators of cell differentiation, tissue development, and energy metabolism. Given their central roles in sensing the cellular metabolic state and controlling metabolic homeostasis, PPARs became important targets of drug [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and they are essential regulators of cell differentiation, tissue development, and energy metabolism. Given their central roles in sensing the cellular metabolic state and controlling metabolic homeostasis, PPARs became important targets of drug development for the management of metabolic disorders. The function of PPARs is mainly regulated through ligand binding, which induces structural changes, further affecting the interactions with co-activators or co-repressors to stimulate or inhibit their functions. In addition, PPAR functions are also regulated by various Post-translational modifications (PTMs). These PTMs include phosphorylation, SUMOylation, ubiquitination, acetylation, and O-GlcNAcylation, which are found at numerous modification sites. The addition of these PTMs has a wide spectrum of consequences on protein stability, transactivation function, and co-factor interaction. Moreover, certain PTMs in PPAR proteins have been associated with the status of metabolic diseases. In this review, we summarize the PTMs found on the three PPAR isoforms PPARα, PPARβ/δ, and PPARγ, and their corresponding modifying enzymes. We also discuss the functional roles of these PTMs in regulating metabolic homeostasis and provide a perspective for future research in this intriguing field. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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25 pages, 544 KiB  
Review
Metabolic Dysfunction and Peroxisome Proliferator-Activated Receptors (PPAR) in Multiple Sclerosis
by Véronique Ferret-Sena, Carlos Capela and Armando Sena
Int. J. Mol. Sci. 2018, 19(6), 1639; https://doi.org/10.3390/ijms19061639 - 1 Jun 2018
Cited by 17 | Viewed by 6013
Abstract
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS) probably caused, in most cases, by the interaction of genetic and environmental factors. This review first summarizes some clinical, epidemiological and pathological characteristics of MS. Then, the involvement [...] Read more.
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS) probably caused, in most cases, by the interaction of genetic and environmental factors. This review first summarizes some clinical, epidemiological and pathological characteristics of MS. Then, the involvement of biochemical pathways is discussed in the development and repair of the CNS lesions and the immune dysfunction in the disease. Finally, the potential roles of peroxisome proliferator-activated receptors (PPAR) in MS are discussed. It is suggested that metabolic mechanisms modulated by PPAR provide a window to integrate the systemic and neurological events underlying the pathogenesis of the disease. In conclusion, the reviewed data highlight molecular avenues of understanding MS that may open new targets for improved therapies and preventive strategies for the disease. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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16 pages, 877 KiB  
Review
Regulation of Immune Cell Function by PPARs and the Connection with Metabolic and Neurodegenerative Diseases
by Gwenaëlle Le Menn and Jaap G. Neels
Int. J. Mol. Sci. 2018, 19(6), 1575; https://doi.org/10.3390/ijms19061575 - 25 May 2018
Cited by 44 | Viewed by 5076
Abstract
Increasing evidence points towards the existence of a bidirectional interconnection between metabolic disease and neurodegenerative disorders, in which inflammation is linking both together. Activation of members of the peroxisome proliferator-activated receptor (PPAR) family has been shown to have beneficial effects in these interlinked [...] Read more.
Increasing evidence points towards the existence of a bidirectional interconnection between metabolic disease and neurodegenerative disorders, in which inflammation is linking both together. Activation of members of the peroxisome proliferator-activated receptor (PPAR) family has been shown to have beneficial effects in these interlinked pathologies, and these improvements are often attributed to anti-inflammatory effects of PPAR activation. In this review, we summarize the role of PPARs in immune cell function, with a focus on macrophages and T cells, and how this was shown to contribute to obesity-associated inflammation and insulin resistance, atherosclerosis, and neurodegenerative disorders. We address gender differences as a potential explanation in observed contradictory results, and we highlight PPAR-induced metabolic changes as a potential mechanism of regulation of immune cell function through these nuclear receptors. Together, immune cell-specific activation of PPARs present a promising therapeutic approach to treat both metabolic and neurodegenerative diseases. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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16 pages, 666 KiB  
Review
The CD36-PPARγ Pathway in Metabolic Disorders
by Loïze Maréchal, Maximilien Laviolette, Amélie Rodrigue-Way, Baly Sow, Michèle Brochu, Véronique Caron and André Tremblay
Int. J. Mol. Sci. 2018, 19(5), 1529; https://doi.org/10.3390/ijms19051529 - 21 May 2018
Cited by 105 | Viewed by 15293
Abstract
Uncovering the biological role of nuclear receptor peroxisome proliferator-activated receptors (PPARs) has greatly advanced our knowledge of the transcriptional control of glucose and energy metabolism. As such, pharmacological activation of PPARγ has emerged as an efficient approach for treating metabolic disorders with the [...] Read more.
Uncovering the biological role of nuclear receptor peroxisome proliferator-activated receptors (PPARs) has greatly advanced our knowledge of the transcriptional control of glucose and energy metabolism. As such, pharmacological activation of PPARγ has emerged as an efficient approach for treating metabolic disorders with the current use of thiazolidinediones to improve insulin resistance in diabetic patients. The recent identification of growth hormone releasing peptides (GHRP) as potent inducers of PPARγ through activation of the scavenger receptor CD36 has defined a novel alternative to regulate essential aspects of lipid and energy metabolism. Recent advances on the emerging role of CD36 and GHRP hexarelin in regulating PPARγ downstream actions with benefits on atherosclerosis, hepatic cholesterol biosynthesis and fat mitochondrial biogenesis are summarized here. The response of PPARγ coactivator PGC-1 is also discussed in these effects. The identification of the GHRP-CD36-PPARγ pathway in controlling various tissue metabolic functions provides an interesting option for metabolic disorders. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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14 pages, 453 KiB  
Review
The Role of Peroxisome Proliferator-Activated Receptors and Their Transcriptional Coactivators Gene Variations in Human Trainability: A Systematic Review
by Miroslav Petr, Petr Stastny, Adam Zajac, James J. Tufano and Agnieszka Maciejewska-Skrendo
Int. J. Mol. Sci. 2018, 19(5), 1472; https://doi.org/10.3390/ijms19051472 - 15 May 2018
Cited by 36 | Viewed by 5315
Abstract
Background: The peroxisome proliferator-activated receptors (PPARA, PPARG, PPARD) and their transcriptional coactivators’ (PPARGC1A, PPARGC1B) gene polymorphisms have been associated with muscle morphology, oxygen uptake, power output and endurance performance. The purpose of this review is to [...] Read more.
Background: The peroxisome proliferator-activated receptors (PPARA, PPARG, PPARD) and their transcriptional coactivators’ (PPARGC1A, PPARGC1B) gene polymorphisms have been associated with muscle morphology, oxygen uptake, power output and endurance performance. The purpose of this review is to determine whether the PPARs and/or their coactivators’ polymorphisms can predict the training response to specific training stimuli. Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses, a literature review has been run for a combination of PPARs and physical activity key words. Results: All ten of the included studies were performed using aerobic training in general, sedentary or elderly populations from 21 to 75 years of age. The non-responders for aerobic training (VO2peak increase, slow muscle fiber increase and low-density lipoprotein decrease) are the carriers of PPARGC1A rs8192678 Ser/Ser. The negative responders for aerobic training (decrease in VO2peak) are carriers of the PPARD rs2267668 G allele. The negative responders for aerobic training (decreased glucose tolerance and insulin response) are subjects with the PPARG rs1801282 Pro/Pro genotype. The best responders to aerobic training are PPARGC1A rs8192678 Gly/Gly, PPARD rs1053049 TT, PPARD rs2267668 AA and PPARG rs1801282 Ala carriers. Conclusions: The human response for aerobic training is significantly influenced by PPARs’ gene polymorphism and their coactivators, where aerobic training can negatively influence glucose metabolism and VO2peak in some genetically-predisposed individuals. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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28 pages, 6051 KiB  
Review
An aPPARent Functional Consequence in Skeletal Muscle Physiology via Peroxisome Proliferator-Activated Receptors
by Wendy Wen Ting Phua, Melissa Xin Yu Wong, Zehuan Liao and Nguan Soon Tan
Int. J. Mol. Sci. 2018, 19(5), 1425; https://doi.org/10.3390/ijms19051425 - 10 May 2018
Cited by 52 | Viewed by 9509
Abstract
Skeletal muscle comprises 30–40% of the total body mass and plays a central role in energy homeostasis in the body. The deregulation of energy homeostasis is a common underlying characteristic of metabolic syndrome. Over the past decades, peroxisome proliferator-activated receptors (PPARs) have been [...] Read more.
Skeletal muscle comprises 30–40% of the total body mass and plays a central role in energy homeostasis in the body. The deregulation of energy homeostasis is a common underlying characteristic of metabolic syndrome. Over the past decades, peroxisome proliferator-activated receptors (PPARs) have been shown to play critical regulatory roles in skeletal muscle. The three family members of PPAR have overlapping roles that contribute to the myriad of processes in skeletal muscle. This review aims to provide an overview of the functions of different PPAR members in energy homeostasis as well as during skeletal muscle metabolic disorders, with a particular focus on human and relevant mouse model studies. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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17 pages, 7774 KiB  
Review
The Role of PPAR and Its Cross-Talk with CAR and LXR in Obesity and Atherosclerosis
by Pengfei Xu, Yonggong Zhai and Jing Wang
Int. J. Mol. Sci. 2018, 19(4), 1260; https://doi.org/10.3390/ijms19041260 - 23 Apr 2018
Cited by 79 | Viewed by 13029
Abstract
The prevalence of obesity and atherosclerosis has substantially increased worldwide over the past several decades. Peroxisome proliferator-activated receptors (PPARs), as fatty acids sensors, have been therapeutic targets in several human lipid metabolic diseases, such as obesity, atherosclerosis, diabetes, hyperlipidaemia, and non-alcoholic fatty liver [...] Read more.
The prevalence of obesity and atherosclerosis has substantially increased worldwide over the past several decades. Peroxisome proliferator-activated receptors (PPARs), as fatty acids sensors, have been therapeutic targets in several human lipid metabolic diseases, such as obesity, atherosclerosis, diabetes, hyperlipidaemia, and non-alcoholic fatty liver disease. Constitutive androstane receptor (CAR) and liver X receptors (LXRs) were also reported as potential therapeutic targets for the treatment of obesity and atherosclerosis, respectively. Further clarification of the internal relationships between these three lipid metabolic nuclear receptors is necessary to enable drug discovery. In this review, we mainly summarized the cross-talk of PPARs-CAR in obesity and PPARs-LXRs in atherosclerosis. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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26 pages, 6757 KiB  
Review
Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches
by Alexandre Vallée, Yves Lecarpentier, Rémy Guillevin and Jean-Noël Vallée
Int. J. Mol. Sci. 2018, 19(4), 1212; https://doi.org/10.3390/ijms19041212 - 16 Apr 2018
Cited by 44 | Viewed by 7411
Abstract
Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/β-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in [...] Read more.
Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/β-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in MS between the canonical WNT/β-catenin pathway and PPARγ and their reprogramming energy metabolism implications. Demyelination in MS is associated with chronic inflammation, which is itself associated with the release of cytokines by CD4+ Th17 cells, and downregulation of PPARγ expression leading to the upregulation of the WNT/β-catenin pathway. Upregulation of WNT/β-catenin signaling induces activation of glycolytic enzymes that modify their energy metabolic behavior. Then, in MS cells, a large portion of cytosolic pyruvate is converted into lactate. This phenomenon is called the Warburg effect, despite the availability of oxygen. The Warburg effect is the shift of an energy transfer production from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lactate production is correlated with increased WNT/β-catenin signaling and demyelinating processes by inducing dysfunction of CD4+ T cells leading to axonal and neuronal damage. In MS, downregulation of PPARγ decreases insulin sensitivity and increases neuroinflammation. PPARγ agonists inhibit Th17 differentiation in CD4+ T cells and then diminish release of cytokines. In MS, abnormalities in the regulation of circadian rhythms stimulate the WNT pathway to initiate the demyelination process. Moreover, PPARγ contributes to the regulation of some key circadian genes. Thus, PPARγ agonists interfere with reprogramming energy metabolism by directly inhibiting the WNT/β-catenin pathway and circadian rhythms and could appear as promising treatments in MS due to these interactions. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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21 pages, 3116 KiB  
Review
PPAR Agonists and Metabolic Syndrome: An Established Role?
by Margherita Botta, Matteo Audano, Amirhossein Sahebkar, Cesare R. Sirtori, Nico Mitro and Massimiliano Ruscica
Int. J. Mol. Sci. 2018, 19(4), 1197; https://doi.org/10.3390/ijms19041197 - 14 Apr 2018
Cited by 172 | Viewed by 15654
Abstract
Therapeutic approaches to metabolic syndrome (MetS) are numerous and may target lipoproteins, blood pressure or anthropometric indices. Peroxisome proliferator-activated receptors (PPARs) are involved in the metabolic regulation of lipid and lipoprotein levels, i.e., triglycerides (TGs), blood glucose, and abdominal adiposity. PPARs may be [...] Read more.
Therapeutic approaches to metabolic syndrome (MetS) are numerous and may target lipoproteins, blood pressure or anthropometric indices. Peroxisome proliferator-activated receptors (PPARs) are involved in the metabolic regulation of lipid and lipoprotein levels, i.e., triglycerides (TGs), blood glucose, and abdominal adiposity. PPARs may be classified into the α, β/δ and γ subtypes. The PPAR-α agonists, mainly fibrates (including newer molecules such as pemafibrate) and omega-3 fatty acids, are powerful TG-lowering agents. They mainly affect TG catabolism and, particularly with fibrates, raise the levels of high-density lipoprotein cholesterol (HDL-C). PPAR-γ agonists, mainly glitazones, show a smaller activity on TGs but are powerful glucose-lowering agents. Newer PPAR-α/δ agonists, e.g., elafibranor, have been designed to achieve single drugs with TG-lowering and HDL-C-raising effects, in addition to the insulin-sensitizing and antihyperglycemic effects of glitazones. They also hold promise for the treatment of non-alcoholic fatty liver disease (NAFLD) which is closely associated with the MetS. The PPAR system thus offers an important hope in the management of atherogenic dyslipidemias, although concerns regarding potential adverse events such as the rise of plasma creatinine, gallstone formation, drug–drug interactions (i.e., gemfibrozil) and myopathy should also be acknowledged. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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14 pages, 1266 KiB  
Review
Pivotal Roles of Peroxisome Proliferator-Activated Receptors (PPARs) and Their Signal Cascade for Cellular and Whole-Body Energy Homeostasis
by Shreekrishna Lamichane, Babita Dahal Lamichane and Sang-Mo Kwon
Int. J. Mol. Sci. 2018, 19(4), 949; https://doi.org/10.3390/ijms19040949 - 22 Mar 2018
Cited by 99 | Viewed by 8770
Abstract
Peroxisome proliferator-activated receptors (PPARs), members of the nuclear receptor superfamily, are important in whole-body energy metabolism. PPARs are classified into three isoforms, namely, PPARα, β/δ, and γ. They are collectively involved in fatty acid oxidation, as well as glucose and lipid metabolism throughout [...] Read more.
Peroxisome proliferator-activated receptors (PPARs), members of the nuclear receptor superfamily, are important in whole-body energy metabolism. PPARs are classified into three isoforms, namely, PPARα, β/δ, and γ. They are collectively involved in fatty acid oxidation, as well as glucose and lipid metabolism throughout the body. Importantly, the three isoforms of PPARs have complementary and distinct metabolic activities for energy balance at a cellular and whole-body level. PPARs also act with other co-regulators to maintain energy homeostasis. When endogenous ligands bind with these receptors, they regulate the transcription of genes involved in energy homeostasis. However, the exact molecular mechanism of PPARs in energy metabolism remains unclear. In this review, we summarize the importance of PPAR signals in multiple organs and focus on the pivotal roles of PPAR signals in cellular and whole-body energy homeostasis. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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14 pages, 1337 KiB  
Review
PPARβ/δ: A Key Therapeutic Target in Metabolic Disorders
by Xavier Palomer, Emma Barroso, Javier Pizarro-Delgado, Lucía Peña, Gaia Botteri, Mohammad Zarei, David Aguilar, Marta Montori-Grau and Manuel Vázquez-Carrera
Int. J. Mol. Sci. 2018, 19(3), 913; https://doi.org/10.3390/ijms19030913 - 20 Mar 2018
Cited by 71 | Viewed by 7054
Abstract
Research in recent years on peroxisome proliferator-activated receptor (PPAR)β/δ indicates that it plays a key role in the maintenance of energy homeostasis, both at the cellular level and within the organism as a whole. PPARβ/δ activation might help prevent the development of metabolic [...] Read more.
Research in recent years on peroxisome proliferator-activated receptor (PPAR)β/δ indicates that it plays a key role in the maintenance of energy homeostasis, both at the cellular level and within the organism as a whole. PPARβ/δ activation might help prevent the development of metabolic disorders, including obesity, dyslipidaemia, type 2 diabetes mellitus and non-alcoholic fatty liver disease. This review highlights research findings on the PPARβ/δ regulation of energy metabolism and the development of diseases related to altered cellular and body metabolism. It also describes the potential of the pharmacological activation of PPARβ/δ as a treatment for human metabolic disorders. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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Lysophospholipid-Related Diseases and PPARγ Signaling Pathway
by Tamotsu Tsukahara, Yoshikazu Matsuda and Hisao Haniu
Int. J. Mol. Sci. 2017, 18(12), 2730; https://doi.org/10.3390/ijms18122730 - 16 Dec 2017
Cited by 34 | Viewed by 7042
Abstract
The nuclear receptor superfamily includes ligand-inducible transcription factors that play diverse roles in cell metabolism and are associated with pathologies such as cardiovascular diseases. Lysophosphatidic acid (LPA) belongs to a family of lipid mediators. LPA and its naturally occurring analogues interact with G [...] Read more.
The nuclear receptor superfamily includes ligand-inducible transcription factors that play diverse roles in cell metabolism and are associated with pathologies such as cardiovascular diseases. Lysophosphatidic acid (LPA) belongs to a family of lipid mediators. LPA and its naturally occurring analogues interact with G protein-coupled receptors on the cell surface and an intracellular nuclear hormone receptor. In addition, several enzymes that utilize LPA as a substrate or generate it as a product are under its regulatory control. Recent studies have demonstrated that the endogenously produced peroxisome proliferator-activated receptor gamma (PPARγ) antagonist cyclic phosphatidic acid (cPA), which is structurally similar to LPA, inhibits cancer cell invasion and metastasis in vitro and in vivo. We recently observed that cPA negatively regulates PPARγ function by stabilizing the binding of the co-repressor protein, a silencing mediator of retinoic acid, and the thyroid hormone receptor. We also showed that cPA prevents neointima formation, adipocyte differentiation, lipid accumulation, and upregulation of PPARγ target gene transcription. The present review discusses the arbitrary aspects of the physiological and pathophysiological actions of lysophospholipids in vascular and nervous system biology. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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