New trends in the pharmacological intervention of PPARs in obesity: Role of natural and synthetic compounds_

: Obesity is a major health concern for a growing fraction of the population, with the prevalence of obesity and its related metabolic disorders not being fully understood. Over the last decade, many attempts have been undertaken to understand the mechanisms at the basis of this condition, in which the accumulation of fat occurring in adipose tissue, leads to the pathogenesis of obesity related disorders. Among the most recent studies, those on Peroxisome Proliferator Activated Receptors (PPARs) revealed that these nuclear receptor proteins acting as transcription factors, among others, regulate the expression of genes involved in energy, lipid, and glucose metabolisms, and chronic inflammation. The three different isotypes of PPARs, with different tissue expression and ligand binding specificity, exert similar or overlapping functions directly or indirectly linked to obesity. In this study, we reviewed the available scientific reports concerning the PPARs structure and functions, especially in obesity, considering both natural and synthetic ligands and their role in the therapy of obesity and obesity-associated disorders. In the whole, the collected data show that there are both natural and synthetic compounds that show beneficial promising activity as PPAR agonists in chronic diseases related to obesity.

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The Journey of Thiazolidinediones as Modulators of PPARs for the Management of Diabetes: A Current Perspective

Current Pharmaceutical Design ◽

10.2174/1381612825666190716094852 ◽

2019 ◽

Vol 25 (23) ◽

pp. 2540-2554 ◽

Cited By ~ 5

Author(s):

Waquar Ahsan

Keyword(s):

Peroxisome Proliferator ◽

Expression Of Genes ◽

Current Perspective ◽

Drug Designing ◽

Peroxisome Proliferator Activated Receptors ◽

To Come ◽

Ppar Ligands ◽

A Current

Peroxisome Proliferator-Activated Receptors (PPARs) also known as glitazone receptors are a family of receptors that regulate the expression of genes and have an essential role in carbohydrate, lipid and protein metabolism apart from other functions. PPARs come in 3 sub-types: PPAR-α, PPAR-β/δ and PPAR-γ - with PPAR-γ having 2 isoforms - γ1 and γ2. Upon activation, the PPARs regulate the transcription of various genes involved in lipid and glucose metabolism, adipocyte differentiation, increasing insulin sensitivity, prevention of oxidative stress and to a certain extent, modulation of immune responses via macrophages that have been implicated in the pathogenesis of insulin resistance. Hence, PPARs are an attractive molecular target for designing new anti-diabetic drugs. This has led to a boost in the research efforts directed towards designing of PPAR ligands - particularly ones that can selectively and specifically activate one or more of the PPAR subtypes. Though, PPAR- γ full agonists such as Thiazolidinediones (TZDs) are well established agents for dyslipidemia and type 2 diabetes mellitus (T2D), the side effect profile associated with TZDs has potentiated an imminent need to come up with newer agents that act through this pathway. Several newer derivatives having TZD scaffold have been designed using structure based drug designing technique and computational tools and tested for their PPAR binding affinity and efficacy in combating T2D and some have shown promising activities. This review would focus on the role of PPARs in the management of T2D; recently reported TZD derivatives which acted as agonists of PPAR- γ and its subtypes and are potentially useful in the new drug discovery for the disease.

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New Insights into the Role of Peroxisome Proliferator-Activated Receptors in Regulating the Inflammatory Response after Tissue Injury

PPAR Research ◽

10.1155/2012/728461 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 29

Author(s):

Miriam D. Neher ◽

Sebastian Weckbach ◽

Markus S. Huber-Lang ◽

Philip F. Stahel

Keyword(s):

Inflammatory Response ◽

Major Trauma ◽

Tissue Injury ◽

Ischemia Reperfusion ◽

Healing Process ◽

Wound Healing Process ◽

Peroxisome Proliferator ◽

Ppar Agonists ◽

Peroxisome Proliferator Activated Receptors

Major trauma results in a strong inflammatory response in injured tissue. This posttraumatic hyperinflammation has been implied in the adverse events leading to a breakdown of host defense mechanisms and ultimately to delayed organ failure. Ligands to peroxisome proliferator-activated receptors (PPARs) have recently been identified as potent modulators of inflammation in various acute and chronic inflammatory conditions. The main mechanism of action mediated by ligand binding to PPARs is the inhibition of the nuclear transcription factor NF-κB, leading to downregulation of downstream gene transcription, such as for genes encoding proinflammatory cytokines. Pharmacological PPAR agonists exert strong anti-inflammatory properties in various animal models of tissue injury, including central nervous system trauma, ischemia/reperfusion injury, sepsis, and shock. In addition, PPAR agonists have been shown to induce wound healing process after tissue trauma. The present review was designed to provide an up-to-date overview on the current understanding of the role of PPARs in the pathophysiology of the inflammatory response after major trauma. Therapeutic options for using recombinant PPAR agonists as pharmacological agents in the management of posttraumatic inflammation will be discussed.

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Role of PPARs inTrypanosoma cruziInfection: Implications for Chagas Disease Therapy

PPAR Research ◽

10.1155/2012/528435 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Eugenia Hovsepian ◽

Federico Penas ◽

Gerardo A. Mirkin ◽

Nora B. Goren

Keyword(s):

Chagas Disease ◽

Health Concern ◽

Peroxisome Proliferator ◽

Cytokines And Chemokines ◽

Disease Therapy ◽

Host Health ◽

Peroxisome Proliferator Activated Receptors ◽

Ppar Ligands ◽

Precise Role

Chagas disease, which is caused byTrypanosoma cruzi(T. cruzi), remains a substantial public health concern and an important cause of morbidity and mortality in Latin America.T. cruziinfection causes an intense inflammatory response in diverse tissues by triggering local expression of inflammatory mediators, which results in the upregulation of the levels of cytokines and chemokines, and important cardiac alterations in the host, being one of the most characteristic damages of Chagas disease. Therefore, controlling the inflammatory reaction becomes critical for the control of the proliferation of the parasite and of the evolution of Chagas disease. The nuclear receptors known as peroxisome proliferator-activated receptors (PPARs) have emerged as key regulators of lipid metabolism and inflammation. The precise role of PPAR ligands inT. cruziinfection or in Chagas disease is poorly understood. This review summarizes our knowledge aboutT. cruziinfection as well as about the activation of PPARs and the potential role of their ligands in the resolution of inflammation, with the aim to address a new pharmacological approach to improve the host health.

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Enhanced Hepatocarcinogenicity Due to Agonists of Peroxisome Proliferator-Activated Receptors in Senescent Rats: Role of Peroxisome Proliferation, Cell Proliferation, and Apoptosis

The Scientific World JOURNAL ◽

10.1100/tsw.2002.352 ◽

2002 ◽

Vol 2 ◽

pp. 1491-1500 ◽

Cited By ~ 9

Author(s):

Jihan Youssef ◽

Mostafa Badr

Keyword(s):

Cell Proliferation ◽

Peroxisome Proliferator ◽

Carcinogenic Effect ◽

Peroxisome Proliferator Activated Receptor ◽

New Findings ◽

Proliferation And Apoptosis ◽

Ppar Agonists ◽

Old Rats ◽

Peroxisome Proliferator Activated Receptors

Exposure to agonists of peroxisome proliferator-activated receptor alpha (PPARα) causes liver cancer in rodents, with aged animals being more susceptible than their younger counterparts to this effect. Treatment with these chemicals produced a five- to sevenfold higher yield of grossly visible hepatic tumors in old rats compared to young animals. The enhanced susceptibility of the aged livers to the carcinogenic effect of PPAR agonists could not be explained by differences in levels of peroxisomal and/or cell proliferation between young and old animals, as neither of these responses was exaggerated with aging. Reported studies have shown that activating PPARa results in the suppression of hepatic apoptosis. This effect is expected to diminish the ability of the liver to purge itself of pre-existing neoplastic cells, allowing them to progress to tumors. New findings from our laboratories show that the aged liver is exceedingly sensitive to the antiapoptotic effect of PPAR agonists. In addition, aged livers showed remarkably higher levels of the antiapoptotic protein Bcl-2 than livers of young, adult, and middle-aged animals. Interestingly, the PPARa agonist Wy-14,643 significantly diminished elements of the proapoptotic machinery (e.g., Bax, caspases, and fas) in the aged liver, while remarkably increasing elements of this machinery in younger animals. Taken together, while activation of PPARs appears to inhibit apoptosis in livers of senescent animals, activating these receptors seems to stimulate the apoptotic machinery in young animals. This paradoxical effect may be responsible for the exaggerated sensitivity of the aged liver to the carcinogenic effect of agents that activate PPARs.

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PPARs, Obesity, and Inflammation

PPAR Research ◽

10.1155/2007/95974 ◽

2007 ◽

Vol 2007 ◽

pp. 1-10 ◽

Cited By ~ 132

Author(s):

Rinke Stienstra ◽

Caroline Duval ◽

Michael Müller ◽

Sander Kersten

Keyword(s):

Adipose Tissue ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Vascular Wall ◽

Peroxisome Proliferator ◽

Proinflammatory Mediators ◽

Inflammatory Status ◽

Prevalence Of Obesity ◽

Peroxisome Proliferator Activated Receptors

The worldwide prevalence of obesity and related metabolic disorders is rising rapidly, increasing the burden on our healthcare system. Obesity is often accompanied by excess fat storage in tissues other than adipose tissue, including liver and skeletal muscle, which may lead to local insulin resistance and may stimulate inflammation, as in steatohepatitis. In addition, obesity changes the morphology and composition of adipose tissue, leading to changes in protein production and secretion. Some of these secreted proteins, including several proinflammatory mediators, may be produced by macrophages resident in the adipose tissue. The changes in inflammatory status of adipose tissue and liver with obesity feed a growing recognition that obesity represents a state of chronic low-level inflammation. Various molecular mechanisms have been implicated in obesity-induced inflammation, some of which are modulated by the peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated transcription factors involved in the regulation of numerous biological processes, including lipid and glucose metabolism, and overall energy homeostasis. Importantly, PPARs also modulate the inflammatory response, which makes them an interesting therapeutic target to mitigate obesity-induced inflammation and its consequences. This review will address the role of PPARs in obesity-induced inflammation specifically in adipose tissue, liver, and the vascular wall.

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Role of peroxisome proliferator-activated receptors in the control of alcohol dependence and concomitant liver pathology

Proceedings of the National Academy of Sciences of Belarus Medical series ◽

10.29235/1814-6023-2019-16-2-244-256 ◽

2019 ◽

Vol 16 (2) ◽

pp. 244-256

Author(s):

I. N. Semenenya ◽

A. H. Shlyahtun ◽

H. F. Raduta

Keyword(s):

Liver Disease ◽

Alcohol Dependence ◽

Alcoholic Liver Disease ◽

Therapeutic Potential ◽

Scattered Data ◽

Peroxisome Proliferator ◽

Liver Pathology ◽

Ppar Agonists ◽

Peroxisome Proliferator Activated Receptors

The article is aimed to summarize the scattered data on the role of peroxisome proliferator-activated receptors (PPAR) and the possibility of using PPAR’s agonists for treatment of alcohol dependence and alcoholic liver disease. Earlier it was shown that some PPAR agonists can reduce ethanol consumption and preference in rodents. Several hypotheses considering the antialcoholic activity of PPAR agonists and the roles of PPAR in the development of alcohol dependence were discussed. In light of these data, the therapeutic potential of PPARs agonists as an agent for the treatment of alcoholism, has been reviewed.

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Parsing the Role of PPARs in Macrophage Processes

Frontiers in Immunology ◽

10.3389/fimmu.2021.783780 ◽

2021 ◽

Vol 12 ◽

Author(s):

Daniel Toobian ◽

Pradipta Ghosh ◽

Gajanan D. Katkar

Keyword(s):

Cell Function ◽

Immune Cell ◽

Inflammatory Diseases ◽

Chronic Inflammatory Disease ◽

Peroxisome Proliferator ◽

Microbial Infection ◽

Ppar Agonists ◽

Peroxisome Proliferator Activated Receptors ◽

Nuclear Receptor Family

Cells are richly equipped with nuclear receptors, which act as ligand-regulated transcription factors. Peroxisome proliferator activated receptors (PPARs), members of the nuclear receptor family, have been extensively studied for their roles in development, differentiation, and homeostatic processes. In the recent past, there has been substantial interest in understanding and defining the functions of PPARs and their agonists in regulating innate and adaptive immune responses as well as their pharmacologic potential in combating acute and chronic inflammatory disease. In this review, we focus on emerging evidence of the potential roles of the PPAR subtypes in macrophage biology. We also discuss the roles of dual and pan PPAR agonists as modulators of immune cell function, microbial infection, and inflammatory diseases.

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The Functions of PPARs in Aging and Longevity

PPAR Research ◽

10.1155/2007/39654 ◽

2007 ◽

Vol 2007 ◽

pp. 1-10 ◽

Cited By ~ 16

Author(s):

Adnan Erol

Keyword(s):

Oxidative Stress ◽

Aging Process ◽

Peroxisome Proliferator ◽

Clinical Use ◽

Age Related ◽

Therapeutic Uses ◽

Ppar Agonists ◽

Peroxisome Proliferator Activated Receptors ◽

And Oxidative Stress

Peroxisome proliferator-activated receptors (PPARs) are key regulators in various age-associated pathophysiological processes related to energy metabolism and oxidative stress. A progressive rise of oxidative stress and related inflammatory reaction appears the hallmarks of the aging process and many age-related diseases. PPARs are important redox-sensitive transcription factors and their dyregulated activations seem to be major culprits for these pathological processes. Drugs targeting PPARs activity are already in widespread clinical use; however, based on these concepts, this review highlights the understanding of the role of PPARs in aging and indicates the necessary particular attention for the potential therapeutic uses of current PPAR agonists in age-associated diseases.

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Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

Cells ◽

10.3390/cells10030629 ◽

2021 ◽

Vol 10 (3) ◽

pp. 629

Author(s):

Jorge Gutiérrez-Cuevas ◽

Ana Sandoval-Rodriguez ◽

Alejandra Meza-Rios ◽

Hugo Christian Monroy-Ramírez ◽

Marina Galicia-Moreno ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Dysfunction ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Peroxisome Proliferator ◽

White Adipocyte ◽

Peroxisome Proliferator Activated Receptors ◽

And Oxidative Stress

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

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Depdc5 deficiency exacerbates alcohol-induced hepatic steatosis via suppression of PPARα pathway

Cell Death and Disease ◽

10.1038/s41419-021-03980-6 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Lin Xu ◽

Xinge Zhang ◽

Yue Xin ◽

Jie Ma ◽

Chenyan Yang ◽

...

Keyword(s):

Liver Injury ◽

Hepatic Steatosis ◽

Liver Steatosis ◽

Pharmacological Intervention ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Pathological Effect ◽

Mtorc1 Pathway

AbstractAlcohol-related liver disease (ALD), a condition caused by alcohol overconsumption, occurs in three stages of liver injury including steatosis, hepatitis, and cirrhosis. DEP domain-containing protein 5 (DEPDC5), a component of GAP activities towards Rags 1 (GATOR1) complex, is a repressor of amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In the current study, we found that aberrant activation of mTORC1 was likely attributed to the reduction of DEPDC5 in the livers of ethanol-fed mice or ALD patients. To further define the in vivo role of DEPDC5 in ALD development, we generated Depdc5 hepatocyte-specific knockout mouse model (Depdc5-LKO) in which mTORC1 pathway was constitutively activated through loss of the inhibitory effect of GATOR1. Hepatic Depdc5 ablation leads to mild hepatomegaly and liver injury and protects against diet-induced liver steatosis. In contrast, ethanol-fed Depdc5-LKO mice developed severe hepatic steatosis and inflammation. Pharmacological intervention with Torin 1 suppressed mTORC1 activity and remarkably ameliorated ethanol-induced hepatic steatosis and inflammation in both control and Depdc5-LKO mice. The pathological effect of sustained mTORC1 activity in ALD may be attributed to the suppression of peroxisome proliferator activated receptor α (PPARα), the master regulator of fatty acid oxidation in hepatocytes, because fenofibrate (PPARα agonist) treatment reverses ethanol-induced liver steatosis and inflammation in Depdc5-LKO mice. These findings provide novel insights into the in vivo role of hepatic DEPDC5 in the development of ALD.

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