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Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of...
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Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of Prof. Walter Wahli

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Enzymology".

Deadline for manuscript submissions: closed (30 December 2024) | Viewed by 20275

Special Issue Editors

Dr. Hervé Guillou

E-Mail Website
Guest Editor
INRAE Toulouse, Toxalim Unit, 180 Chemin de Tournefeuille, BP93173, 31027 Toulouse, CEDEX 3, France
Interests: nuclear receptors; liver; hepatology; NALFD; diabetes; toxicology; systems biology; lipidomic; metabolism; PPAR; FGF21
Prof. Dr. Manuel Vázquez-Carrera

E-Mail Website
Guest Editor
1. Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
2. Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain
3. Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Interests: insulin resistance; PPAR; FGF21; GDF-15; inflammation; type 2 diabetes mellitus; non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); atherogenic dyslipidemia; diabetic cardiomyopathy; skeletal muscle
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Special Issue Information

Dear Colleagues,

Prof. Walter Wahli has spent much of his career exploring and helping to define the functions of Peroxisome Proliferator-Activated Receptors (PPARs). The pioneering work of Dr. Wahli in the field of PPARs started more than 25 years ago. At that time, the idea that “classic” nuclear hormone receptors (e.g., estrogen receptors and glucocorticoid receptors) may belong to a larger superfamily gained momentum. Prof. Wahli’s group started to search for new members of this putative superfamily using the DNA binding domain coding sequence of the estrogen receptor as a probe. Using it as a screening tool of cDNA libraries under low stringency hybridization conditions, they found novel receptors, now called PPARα, β, γ. The first of them, PPARα, was discovered independently and was published first by Isabelle Issemann and Stephen Green, while Walter Wahli and colleagues were characterizing all three isotypes of this PPAR subfamily.

Since this cutting-edge study in the field of PPARs, additional contributions of Walter Wahli and collaborators have unraveled the intricate mechanisms through which PPARs are activated by fatty acids and regulate gene expression in metabolic and physiological pathways. These findings, not least that fatty acids can use nuclear receptor-mediated mechanisms like hormones, reshaped our understanding of metabolic diseases and provided invaluable insights into potential therapeutic avenues using synthetic compounds. Dr. Wahli's exceptional vision and scientific acumen have not only enriched our knowledge of PPAR biology but have also inspired countless researchers to delve deeper into the complexities of these receptors. His legacy will forever endure as an example of excellence, reminding us of the transformative power of scientific inquiry and its potential to improve human health.

We are pleased to invite you to contribute to this Special Issue dedicated to honoring the figure of Prof. Wahli in the field of PPARs by submitting original and review articles focused on the latest developments in the regulation and functions of these nuclear receptors.

We look forward to receiving your contributions. 

Dr. Hervé Guillou
Prof. Dr. Manuel Vázquez-Carrera
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • PPAR
  • nuclear receptors
  • metabolism
  • cancer
  • inflammation
  • pharmacology
  • toxicology

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Published Papers (10 papers)

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15 pages, 4644 KiB  
Article
Docosahexaenoic Acid Supplementation in Postnatal Growth Restricted Rats Does Not Normalize Lung Function or PPARγ Activity
by Adrienne J. Cohen, Wesley R. Chidester, Daniel T. Wray, Nicolette Jessen, Aimee Jones, Cheylah Bitsui, James Zhao, J. Alan Maschek, James E. Cox, Camilia R. Martin and Lisa A. Joss-Moore
Biomolecules 2025, 15(4), 551; https://doi.org/10.3390/biom15040551 - 9 Apr 2025
Viewed by 395
Abstract
The development of BPD in preterm neonates is increased by poor growth and nutritional deficits. The involvement of the fatty acid DHA in the development of BPD has been a focus for over a decade. However, recent clinical trials show that isolated DHA [...] Read more.
The development of BPD in preterm neonates is increased by poor growth and nutritional deficits. The involvement of the fatty acid DHA in the development of BPD has been a focus for over a decade. However, recent clinical trials show that isolated DHA supplementation may increase BPD in subgroups of preterm neonates. One explanation for poor lung outcomes in DHA-supplemented neonates is a disruption of global fatty acid profiles and increased expression of a dominant-negative splice variant of a key driver of lung development, PPARγ. We previously developed a rat model of postnatal growth restriction (PGR) in which pups have impaired lung function and altered PPARγ activity. Here, we use our PGR rat model to assess the effects of DHA supplementation on lung outcomes. We hypothesize that the PPARγ splice variant, PPARγΔ5, will be expressed in the rat lung, and that DHA supplementation of PGR rat pups will alter circulating lipid profiles, lung mechanics, and PPARγ variant expression. Our findings demonstrate that PPARγΔ5 is expressed in the developing rat lung and that DHA supplementation of PGR rat pups alters global circulating fatty-acid profiles and does not normalize PGR-induced impaired lung mechanics or PPARγ activity. Full article
(This article belongs to the Special Issue Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of Prof. Walter Wahli)
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17 pages, 3008 KiB  
Article
Central Actions of Leptin Induce an Atrophic Pattern and Improves Heart Function in Lean Normoleptinemic Rats via PPARβ/δ Activation
by Blanca Rubio, Cristina Pintado, Lorena Mazuecos, Marina Benito, Antonio Andrés and Nilda Gallardo
Biomolecules 2024, 14(8), 1028; https://doi.org/10.3390/biom14081028 - 18 Aug 2024
Viewed by 1168
Abstract
Leptin, acting centrally or peripherally, has complex effects on cardiac remodeling and heart function. We previously reported that central leptin exerts an anti-hypertrophic effect in the heart via cardiac PPARβ/δ activation. Here, we assessed the impact of central leptin administration and PPARβ/δ inhibition [...] Read more.
Leptin, acting centrally or peripherally, has complex effects on cardiac remodeling and heart function. We previously reported that central leptin exerts an anti-hypertrophic effect in the heart via cardiac PPARβ/δ activation. Here, we assessed the impact of central leptin administration and PPARβ/δ inhibition on cardiac function. Various cardiac properties, including QRS duration, R wave amplitude, heart rate (HR), ejection fraction (EF), end-diastolic left ventricular mass (EDLVM), end-diastolic volume (EDV), and cardiac output (CO) were analyzed. Central leptin infusion increased cardiac PPARβ/δ protein content and decreased HR, QRS duration, and R wave amplitude. These changes induced by central leptin suggested a decrease in the ventricular wall growth, which was confirmed by MRI. In fact, the EDLVM was reduced by central leptin while increased in rats co-treated with leptin and GSK0660, a selective antagonist of PPARβ/δ activity. In summary, central leptin plays a dual role in cardiac health, potentially leading to ventricular atrophy and improving heart function when PPARβ/δ signaling is intact. The protective effects of leptin are lost by PPARβ/δ inhibition, underscoring the importance of this pathway. These findings highlight the therapeutic potential of targeting leptin and PPARβ/δ pathways to combat cardiac alterations and heart failure, particularly in the context of obesity. Full article
(This article belongs to the Special Issue Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of Prof. Walter Wahli)
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15 pages, 4602 KiB  
Article
Structural Studies on the Binding Mode of Bisphenols to PPARγ
by Abibe Useini, Inken Kaja Schwerin, Georg Künze and Norbert Sträter
Biomolecules 2024, 14(6), 640; https://doi.org/10.3390/biom14060640 - 30 May 2024
Cited by 1 | Viewed by 1572
Abstract
Bisphenol A (BPA) and bisphenol B (BPB) are widely used in the production of plastics, and their potential adverse health effects, particularly on endocrine disruption and metabolic health, have raised concern. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a pivotal role in metabolic regulation [...] Read more.
Bisphenol A (BPA) and bisphenol B (BPB) are widely used in the production of plastics, and their potential adverse health effects, particularly on endocrine disruption and metabolic health, have raised concern. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a pivotal role in metabolic regulation and adipogenesis, making it a target of interest in understanding the development of obesity and associated health impacts. In this study, we employ X-ray crystallography and molecular dynamics (MD) simulations to study the interaction of PPARγ with BPA and BPB. Crystallographic structures reveal the binding of BPA and BPB to the ligand binding domain of PPARγ, next to C285, where binding of partial agonists as well as antagonists and inverse agonists of PPARγ signaling has been previously observed. However, no interaction of BPA and BPB with Y437 in the activation function 2 site is observed, showing that these ligands cannot stabilize the active conformation of helix 12 directly. Furthermore, free energy analyses of the MD simulations revealed that I341 has a large energetic contribution to the BPA and BPB binding modes characterized in this study. Full article
(This article belongs to the Special Issue Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of Prof. Walter Wahli)
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19 pages, 4508 KiB  
Article
Activation of Peroxisome Proliferator-Activated Receptor-β/δ (PPARβ/δ) in Keratinocytes by Endogenous Fatty Acids
by Bokai Zhu, Xiaoyang Zhu, Michael G. Borland, Douglas H. Ralph, Christopher R. Chiaro, Kristopher W. Krausz, James M. Ntambi, Adam B. Glick, Andrew D. Patterson, Gary H. Perdew, Frank J. Gonzalez and Jeffrey M. Peters
Biomolecules 2024, 14(6), 606; https://doi.org/10.3390/biom14060606 - 21 May 2024
Cited by 1 | Viewed by 2892
Abstract
Nuclear hormone receptors exist in dynamic equilibrium between transcriptionally active and inactive complexes dependent on interactions with ligands, proteins, and chromatin. The present studies examined the hypothesis that endogenous ligands activate peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in keratinocytes. The phorbol ester treatment or HRAS [...] Read more.
Nuclear hormone receptors exist in dynamic equilibrium between transcriptionally active and inactive complexes dependent on interactions with ligands, proteins, and chromatin. The present studies examined the hypothesis that endogenous ligands activate peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in keratinocytes. The phorbol ester treatment or HRAS infection of primary keratinocytes increased fatty acids that were associated with enhanced PPARβ/δ activity. Fatty acids caused PPARβ/δ-dependent increases in chromatin occupancy and the expression of angiopoietin-like protein 4 (Angptl4) mRNA. Analyses demonstrated that stearoyl Co-A desaturase 1 (Scd1) mediates an increase in intracellular monounsaturated fatty acids in keratinocytes that act as PPARβ/δ ligands. The activation of PPARβ/δ with palmitoleic or oleic acid causes arrest at the G2/M phase of the cell cycle of HRAS-expressing keratinocytes that is not found in similarly treated HRAS-expressing Pparb/d-null keratinocytes. HRAS-expressing Scd1-null mouse keratinocytes exhibit enhanced cell proliferation, an effect that is mitigated by treatment with palmitoleic or oleic acid. Consistent with these findings, the ligand activation of PPARβ/δ with GW0742 or oleic acid prevented UVB-induced non-melanoma skin carcinogenesis, an effect that required PPARβ/δ. The results from these studies demonstrate that PPARβ/δ has endogenous roles in keratinocytes and can be activated by lipids found in diet and cellular components. Full article
(This article belongs to the Special Issue Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of Prof. Walter Wahli)
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13 pages, 1593 KiB  
Review
Exploring PPAR Gamma and PPAR Alpha’s Regulation Role in Metabolism via Epigenetics Mechanism
by Małgorzata Małodobra-Mazur, Monika Ołdakowska and Tadeusz Dobosz
Biomolecules 2024, 14(11), 1445; https://doi.org/10.3390/biom14111445 - 13 Nov 2024
Cited by 3 | Viewed by 2933
Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to a family of nuclear receptors. To date, three types of PPARs, namely PPARα, PPARδ, and PPARγ, have been identified, demonstrating co-expression across numerous tissues. PPARγ is primarily distributed in adipose tissue, the colon, the immune system, and [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) belong to a family of nuclear receptors. To date, three types of PPARs, namely PPARα, PPARδ, and PPARγ, have been identified, demonstrating co-expression across numerous tissues. PPARγ is primarily distributed in adipose tissue, the colon, the immune system, and the retina, while PPARα is predominantly expressed in metabolic tissues such as brown adipose tissue, the liver, and the kidneys. Both PPARγ and PPARα play crucial roles in various cellular processes. Recent data suggest that the PPAR family, among other mechanisms, might also be regulated by epigenetic mechanisms. Our recent studies, alongside numerous others, have highlighted the pivotal roles of DNA methylation and histone modifications in the regulation of PPARγ and PPARα, implicating them in the deterioration of metabolic disorders via epigenetic mechanisms. This still not fully understood mechanism of regulation in the nuclear receptors family has been summarized and described in the present paper. The present review summarizes the available data on PPARγ and PPARα regulation via epigenetic mechanisms, elucidating the link between the development of metabolic disorders and the dysregulation of PPARγ and PPARα resulting from these mechanisms. Full article
(This article belongs to the Special Issue Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of Prof. Walter Wahli)
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21 pages, 5248 KiB  
Review
Cladosporols and PPARγ: Same Gun, Same Bullet, More Targets
by Roberta Rapuano, Antonella Mercuri, Sabrina Dallavalle, Salvatore Moricca, Antonio Lavecchia and Angelo Lupo
Biomolecules 2024, 14(8), 998; https://doi.org/10.3390/biom14080998 - 13 Aug 2024
Viewed by 1422
Abstract
Several natural compounds have been found to act as PPARγ agonists, thus regulating numerous biological processes, including the metabolism of carbohydrates and lipids, cell proliferation and differentiation, angiogenesis, and inflammation. Recently, Cladosporols, secondary metabolites purified from the fungus Cladosporium tenuissimum, have been [...] Read more.
Several natural compounds have been found to act as PPARγ agonists, thus regulating numerous biological processes, including the metabolism of carbohydrates and lipids, cell proliferation and differentiation, angiogenesis, and inflammation. Recently, Cladosporols, secondary metabolites purified from the fungus Cladosporium tenuissimum, have been demonstrated to display an efficient ability to control cell proliferation in human colorectal and prostate cancer cells through a PPARγ-mediated modulation of gene expression. In addition, Cladosporols exhibited a strong anti-adipogenetic activity in 3T3-L1 murine preadipocytes, preventing their in vitro differentiation into mature adipocytes. These data interestingly point out that the interaction between Cladosporols and PPARγ, in the milieu of different cells or tissues, might generate a wide range of beneficial effects for the entire organism affected by diabetes, obesity, inflammation, and cancer. This review explores the molecular mechanisms by which the Cladosporol/PPARγ complex may simultaneously interfere with a dysregulated lipid metabolism and cancer promotion and progression, highlighting the potential therapeutic benefits of Cladosporols for human health. Full article
(This article belongs to the Special Issue Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of Prof. Walter Wahli)
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34 pages, 1741 KiB  
Review
PPARs in Clinical Experimental Medicine after 35 Years of Worldwide Scientific Investigations and Medical Experiments
by Anna Skoczyńska, Monika Ołdakowska, Agnieszka Dobosz, Rajmund Adamiec, Sofya Gritskevich, Anna Jonkisz, Arleta Lebioda, Joanna Adamiec-Mroczek, Małgorzata Małodobra-Mazur and Tadeusz Dobosz
Biomolecules 2024, 14(7), 786; https://doi.org/10.3390/biom14070786 - 1 Jul 2024
Cited by 5 | Viewed by 2657
Abstract
This year marks the 35th anniversary of Professor Walter Wahli’s discovery of the PPARs (Peroxisome Proliferator-Activated Receptors) family of nuclear hormone receptors. To mark the occasion, the editors of the scientific periodical Biomolecules decided to publish a special issue in his honor. This [...] Read more.
This year marks the 35th anniversary of Professor Walter Wahli’s discovery of the PPARs (Peroxisome Proliferator-Activated Receptors) family of nuclear hormone receptors. To mark the occasion, the editors of the scientific periodical Biomolecules decided to publish a special issue in his honor. This paper summarizes what is known about PPARs and shows how trends have changed and how research on PPARs has evolved. The article also highlights the importance of PPARs and what role they play in various diseases and ailments. The paper is in a mixed form; essentially it is a review article, but it has been enriched with the results of our experiments. The selection of works was subjective, as there are more than 200,000 publications in the PubMed database alone. First, all papers done on an animal model were discarded at the outset. What remained was still far too large to describe directly. Therefore, only papers that were outstanding, groundbreaking, or simply interesting were described and briefly commented on. Full article
(This article belongs to the Special Issue Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of Prof. Walter Wahli)
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25 pages, 2521 KiB  
Review
New Insights into the Role of PPARγ in Skin Physiopathology
by Stefania Briganti, Sarah Mosca, Anna Di Nardo, Enrica Flori and Monica Ottaviani
Biomolecules 2024, 14(6), 728; https://doi.org/10.3390/biom14060728 - 19 Jun 2024
Cited by 8 | Viewed by 3423
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor expressed in many tissues, including skin, where it is essential for maintaining skin barrier permeability, regulating cell proliferation/differentiation, and modulating antioxidant and inflammatory responses upon ligand binding. Therefore, PPARγ activation has important implications for [...] Read more.
Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor expressed in many tissues, including skin, where it is essential for maintaining skin barrier permeability, regulating cell proliferation/differentiation, and modulating antioxidant and inflammatory responses upon ligand binding. Therefore, PPARγ activation has important implications for skin homeostasis. Over the past 20 years, with increasing interest in the role of PPARs in skin physiopathology, considerable effort has been devoted to the development of PPARγ ligands as a therapeutic option for skin inflammatory disorders. In addition, PPARγ also regulates sebocyte differentiation and lipid production, making it a potential target for inflammatory sebaceous disorders such as acne. A large number of studies suggest that PPARγ also acts as a skin tumor suppressor in both melanoma and non-melanoma skin cancers, but its role in tumorigenesis remains controversial. In this review, we have summarized the current state of research into the role of PPARγ in skin health and disease and how this may provide a starting point for the development of more potent and selective PPARγ ligands with a low toxicity profile, thereby reducing unwanted side effects. Full article
(This article belongs to the Special Issue Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of Prof. Walter Wahli)
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20 pages, 976 KiB  
Review
The Peroxisome Proliferator-Activated Receptors of Ray-Finned Fish: Unique Structures, Elusive Functions
by Evridiki Boukouvala and Grigorios Krey
Biomolecules 2024, 14(6), 634; https://doi.org/10.3390/biom14060634 - 29 May 2024
Cited by 2 | Viewed by 1269
Abstract
The Actinopterygian and specifically the Teleostean peroxisome proliferator-activated receptors (PPARs) present an impressive variability and complexity in their structures, both at the gene and protein levels. These structural differences may also reflect functional divergence from their mammalian homologs, or even between fish species. [...] Read more.
The Actinopterygian and specifically the Teleostean peroxisome proliferator-activated receptors (PPARs) present an impressive variability and complexity in their structures, both at the gene and protein levels. These structural differences may also reflect functional divergence from their mammalian homologs, or even between fish species. This review, taking advantage of the data generated from the whole-genome sequencing of several fish species, highlights the differences in the primary structure of the receptors, while discussing results from the literature pertaining to the functions of fish PPARs and their activation by natural and synthetic compounds. Full article
(This article belongs to the Special Issue Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of Prof. Walter Wahli)
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Other

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13 pages, 2871 KiB  
Hypothesis
Molecular Thumbprints: Biological Signatures That Measure Loss of Identity
by Pallavi R. Devchand, Michael Dicay and John L. Wallace
Biomolecules 2024, 14(10), 1271; https://doi.org/10.3390/biom14101271 - 9 Oct 2024
Viewed by 1009
Abstract
Each life is challenged to adapt to an ever-changing environment with integrity—simply put, to maintain identity. We hypothesize that this mission statement of adaptive homeostasis is particularly poignant in an adaptive response, like inflammation. A maladaptive response of unresolved inflammation can seed chronic [...] Read more.
Each life is challenged to adapt to an ever-changing environment with integrity—simply put, to maintain identity. We hypothesize that this mission statement of adaptive homeostasis is particularly poignant in an adaptive response, like inflammation. A maladaptive response of unresolved inflammation can seed chronic disease over a lifetime. We propose the concept of a molecular thumbprint: a biological signature of loss of identity as a measure of incomplete return to homeostasis after an inflammatory response. Over time, personal molecular thumbprints can measure dynamic and precise trajectories to chronic inflammatory diseases and further loss of self to cancer. Why is this important? Because the phenotypes and molecular signatures of established complex inflammatory diseases are a far cry from the root of the complex problem, let alone the initial seed. Understanding the science behind key germinating seeds of disease helps to identify molecular factors of susceptibility, resilience, and early dietary or drug intervention. We pilot this hypothesis in a rat colitis model that is well-established for understanding molecular mechanisms of colonic health, disease, and transition of colitis to cancer. Full article
(This article belongs to the Special Issue Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of Prof. Walter Wahli)
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