Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas.

The world is experiencing reflections of the intersection of two pandemics: Obesity and coronavirus disease 2019. The prevalence of obesity has tripled since 1975 worldwide, representing substantial public health costs due to its comorbidities. The adipose tissue is the initial site of obesity impairments. During excessive energy intake, it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs. The pancreas is one of the organs most affected by obesity. Once lipotoxicity becomes chronic, there is an increase in insulin secretion by pancreatic beta cells, a surrogate for type 2 diabetes mellitus (T2DM). These alterations threaten the survival of the pancreatic islets, which tend to become dysfunctional, reaching exhaustion in the long term. As for the liver, lipotoxicity favors lipogenesis and impairs beta-oxidation, resulting in hepatic steatosis. This silent disease affects around 30% of the worldwide population and can evolve into end-stage liver disease. Although therapy for hepatic steatosis remains to be defined, peroxisome proliferator-activated receptors (PPARs) activation copes with T2DM management. Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways, leading to insulin resistance relief, improved thermogenesis, and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation. This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases, focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.

Evidence Linking PPARG Genetic Variants with Periodontitis and Type 2 Diabetes Mellitus in a Brazilian Population.

The peroxisome proliferator-activated receptor gamma (PPARG) gene encodes a transcription factor involved in the regulation of complex metabolic and inflammatory diseases. We investigated whether single nucleotide polymorphisms (SNPs) and haplotypes of the PPARG gene could contribute with susceptibility to develop periodontitis alone or together with type 2 diabetes mellitus (T2DM). Moreover, we evaluated the gene-phenotype association by assessing the subjects' biochemical and periodontal parameters, and the expression of PPARG and other immune response-related genes. We examined 345 subjects with a healthy periodontium and without T2DM, 349 subjects with moderate or severe periodontitis but without T2DM, and 202 subjects with moderate or severe periodontitis and T2DM. PPARG SNPs rs12495364, rs1801282, rs1373640, and rs1151999 were investigated. Multiple logistic regressions adjusted for age, sex, and smoking status showed that individuals carrying rs1151999-GG had a 64% lower chance of developing periodontitis together with T2DM. The CCGT haplotype increased the risk of developing periodontitis together with T2DM. The rs1151999-GG and rs12495364-TC were associated with reduced risk of obesity, periodontitis, elevated triglycerides, and elevated glycated hemoglobin, but there was no association with gene expression. Polymorphisms of the PPARG gene were associated with developing periodontitis together with T2DM, and with obesity, lipid, glycemic, and periodontal characteristics.

Leptin signaling in breast cancer and its crosstalk with peroxisome proliferator-activated receptors α and γ.

Obesity may create a mitogenic microenvironment that influences tumor initiation and progression. The obesity-associated adipokine, leptin regulates energy metabolism and has been implicated in cancer development. It has been shown that some cell types other than adipocytes can express leptin and leptin receptors in tumor microenvironments. It has been shown that peroxisome proliferator-activated receptors (PPAR) agonists can affect leptin levels and vice versa leptin can affect PPARs. Activation of PPARs affects the expression of several genes involved in aspects of lipid metabolism. In addition, PPARs regulate cancer cell progression through their action on the tumor cell proliferation, metabolism, and cellular environment. Some studies have shown an association between obesity and several types of cancer, including breast cancer. There is some evidence that suggests that there is crosstalk between PPARs and leptin during the development of breast cancer. Through a systematic review of previous studies, we have reviewed the published relevant articles regarding leptin signaling in breast cancer and its crosstalk with peroxisome proliferator-activated receptors α and γ.

Metabolites of endophytic fungi isolated from leaves of Bauhinia variegata exhibit antioxidant activity and agonist activity on peroxisome proliferator-activated receptors α, ß/δ and γ.

Diabetes mellitus is a metabolic disorder that affects millions of people worldwide and is linked to oxidative stress and inflammation. Thiazolidinediones (TZD) improve insulin sensitization and glucose homeostasis mediated by the activation of peroxisome proliferator-activated receptors γ (PPARγ) in patients with type 2 diabetes. However, their use is associated with severe adverse effects such as loss of bone mass, retention of body fluids, liver and heart problems, and increased risk of bladder cancer. Partial PPARγ agonists can promote the beneficial effects of thiazolidinediones with fewer adverse effects. Endophytic fungi colonize plant tissues and have a particularly active metabolism caused by the interaction with them, which leads to the production of natural products with significant biological effects that may be like that of the colonized plant. Here, we identify seven endophytic fungi isolated from Bauhinia variegata leaves that have antioxidant activities. Also, one of the extracts presented pan-agonist activity on PPAR, and another showed activity in PPARα and PPARß/δ. A better understanding of this relationship could help to comprehend the mechanism of action of antioxidants in treating diabetes and its complications. Moreover, compounds with these capabilities to reduce oxidative stress and activate the receptor that promotes glucose homeostasis are promising candidates in treatment of diabetes.

Invitro effect of pine bark extract on melanin synthesis, tyrosinase activity, production of endothelin-1, and PPAR in cultured melanocytes exposed to Ultraviolet, Infrared, and Visible light radiation.

BACKGROUND: French maritime pine bark (Pinus pinaster) extract (PBE), the registered trade name of which is Pycnogenol® , has been studied for its depigmenting action due to its antioxidant, anti-inflammatory, and anti-melanogenic activity. However, the mechanisms through which PBE are still not fully clear. OBJECTIVE: Evaluate the impact of PBE on four in vitro parameters closely associated with cutaneous pigmentation, including melanin synthesis, tyrosinase activity, endothelin-1 (ED1), and production of peroxisome proliferator-activated receptor α, δ, and γ (PPAR α, δ, and γ), by studying the modulation of action of ultraviolet radiation A (UVA)/ultraviolet radiation B (UVB), infrared-A (IR-A), visible light (VL), and association of UVA/UVB, IR-A, and VL (ASS). METHODS: Human melanocytes were incubated in a dry extract solution of PBE, exposed to UVA/UVB, IR-A, VL, and ASS for subsequent quantification of melanin, ED1, and PPAR α, δ, and γ. The effects of PBE on inhibition of tyrosinase activity were also performed by monophenolase activity assay. RESULTS: UVA/UVB, IR-A, VL, and ASS radiation caused significant increases in the synthesis of melanin, ED1, and PPAR α, δ, and γ when compared to baseline control. However, PBE significantly reduced the production of melanin, ED1, and PPAR α, δ, and γ, as well as reducing about 66.5% of the tyrosinase activity. CONCLUSIONS: PBE reduces in vitro melanin production by downregulating tyrosinase and reducing pigmentation-related mediators, such as ED1 and PPAR α, δ, and γ, therefore contributing to the inhibition of pathways associated with skin hyperpigmentation.

Type II nuclear receptors with potential role in Alzheimer disease.

Nuclear receptors are ligand-activated transcription factors that can modulated cellular processes involved in the development, homeostasis, cell proliferation, metabolism, and reproduction through the control of the specific genetic and molecular program. In the central nervous system, they are key regulators of neural stem cell fate decisions and can modulate the physiology of different brain cells. Over the past decades, a large body of evidence has supported that nuclear receptors are potential therapeutic targets for the treatment of neurodegenerative disorders such as Alzheimer's disease, the most common dementia worldwide, and the main cause of disability in later life. This disease is characterized by the progressive accumulation of amyloid-beta peptides and hyperphosphorylated tau protein that can explain alterations in synaptic transmission and plasticity; loss of dendritic spines; increased in reactive microglia and inflammation; reduction of neuronal stem cells number; myelin and vascular alterations that finally leads to increased neuronal death. Here, we present a review of type II no steroidal nuclear receptors that form obligatory heterodimers with the Retinoid X Receptor (RXR) and its potential in the therapeutic of AD. Activation of type II nuclear receptor by synthetic agonist leads to transcriptional regulation of specific genes that acts counteracting against the detrimental effects of amyloid-beta peptides and hyperphosphorylated tau in neuronal cells recovering the functionality of the synapses. But also, activation of type II nuclear receptor leads to modifications in APP metabolism, repression of inflammatory cascade and inductors of the generation of neuronal stem cells and progenitor cells supporting its potential therapeutics role for Alzheimer's disease.

Understanding Peroxisome Proliferator-Activated Receptors: From the Structure to the Regulatory Actions on Metabolism.

Peroxisome proliferator-activated receptors (PPARs) are multi-domains proteins, belonging to the superfamily of nuclear receptors, which mainly act as ligand-activated transcription factors. A variety of lipophilic molecules, including long-chain polyunsaturated fatty acids and eicosanoids, are capable of binding to PPAR, although the nature of the physiological ligands is still under debate. PPARs regulate the expression of a set of genes involved in glucose and lipid metabolism as well as in the control of inflammatory responses. Herein we review the main molecular and cellular events associated with the activation of PPARs and their effects on metabolism.

Sex-dependent changes in lipid metabolism, PPAR pathways and microRNAs that target PPARs in the fetal liver of rats with gestational diabetes.

Gestational diabetes mellitus (GDM) is a prevalent disease that impairs fetal metabolism and development. We have previously characterized a rat model of GDM induced by developmental programming. Here, we analyzed lipid content, the levels of the three PPAR isotypes and the expression of microRNAs that regulate PPARs expression in the liver of male and female fetuses of control and GDM rats on day 21 of pregnancy. We found increased levels of triglycerides and cholesterol in the livers of male fetuses of GDM rats compared to controls, and, oppositely, reduced levels of triglycerides, cholesterol, phospholipids and free fatty acids in the livers of female fetuses of GDM rats compared to controls. Although GDM did not change PPARα levels in male and female fetal livers, PPARγ was increased in the liver of male fetuses of GDM rats, a change that occurred in parallel to a reduction in the expression of miR-130, a microRNA that targets PPARγ. In livers of female fetuses of GDM rats, no changes in PPARγ and miR-130 were evidenced, but PPARδ was increased, a change that occurred in parallel to a reduction in the expression of miR-9, a microRNA that targets PPARδ, and was unchanged in the liver of male fetuses of GDM and control rats. These results show clear sex-dependent changes in microRNAs that target different PPAR isotypes in relation to changes in the levels of their targets and the differential regulation of lipid metabolism evidenced in fetal livers of GDM pregnancies.

Models of non-Alcoholic Fatty Liver Disease and Potential Translational Value: the Effects of 3,5-L-diiodothyronine.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in industrialized countries and is associated with increased risk of cardiovascular, hepatic and metabolic diseases. Molecular mechanisms on the root of the disrupted lipid homeostasis in NAFLD and potential therapeutic strategies can benefit of in vivo and in vitro experimental models of fatty liver. Here, we describe the high fat diet (HFD)-fed rat in vivo model, and two in vitro models, the primary cultured rat fatty hepatocytes or the FaO rat hepatoma fatty cells, mimicking human NAFLD. Liver steatosis was invariably associated with increased number/size of lipid droplets (LDs) and modulation of expression of genes coding for key genes of lipid metabolism such as peroxisome proliferator-activated receptors (Ppars) and perilipins (Plins). In these models, we tested the anti-steatotic effects of 3,5-L-diiodothyronine (T2), a metabolite of thyroid hormones. T2 markedly reduced triglyceride content and LD size acting on mRNA expression of both Ppars and Plins. T2 also stimulated mitochondrial oxidative metabolism of fatty acids. We conclude that in vivo and especially in vitro models of NAFLD are valuable tools to screen a large number of compounds counteracting the deleterious effect of liver steatosis. Because of the high and negative impact of liver steatosis on human health, ongoing experimental studies from our group are unravelling the ultimate translational value of such cellular models of NAFLD.

Long-chain polyunsaturated fatty acids regulation of PPARs, signaling: Relationship to tissue development and aging.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand-dependent transcription factors that can be activated by different types of fatty acids (FAs). Three isoforms of PPARs have been identify, namely, PPARα, PPARß/δ, and PPARγ, which are able to bind long-chain polyunsaturated FAs (LCPUFAs), n-3 LCPUFAs being bound with greater affinity to achieve activation. FA binding induces a conformational change of the nuclear receptors, triggering the transcription of specific genes including those encoding for various metabolic and cellular processes such as FA ß-oxidation and adipogenesis, thus representing key mediators of lipid homeostasis. In addition, PPARs have important roles during placental, embryonal, and fetal development, and in the regulation of processes related to aging comprising oxidative stress, inflammation, and neuroprotection. The aim of this review was to assess the role of FAs as PPARs ligands, in terms of their main functions associated with FA metabolism and their relevance in the prevention and treatment of related pathologies during human life span.

Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease.

Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease (NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation (mitochondrial and peroxisomal) and microsomal omega-oxidation, being markedly decreased by high-fat (HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs.

HTLV-1 infects human mesenchymal stromal cell in vitro and modifies their phenotypic characteristics.

The typical characteristics of mesenchymal stem cells (MSCs) can be affected by inflammatory microenvironment; however, the exact contribution of HTLV-1 to MSC dysfunction remains to be elucidated. In this study, we demonstrated that MSC cell surface molecules VCAM-1 and ICAM-1 are upregulated by contact with HTLV-1, and HLA-DR was most highly expressed in MSCs co-cultured with MT2 cells. The expression levels of VCAM-1 and HLA-DR were increased in MSCs cultured in the presence of PBMCs isolated from HTLV-1-infected symptomatic individuals compared with those cultured with cells from asymptomatic infected individuals or healthy subjects. HTLV-1 does not impair the MSC differentiation process into osteocytes and adipocytes. In addition, MSCs were efficiently infected with HTLV-1 in vitro through direct contact with HTLV-1-infected cells; however, cell-free virus particles were not capable of causing infection. In summary, HTLV-1 can alter MSC function, and this mechanism may contribute to the pathogenesis of this viral infection.

Mechanism of the anti-platelet effect of natural bioactive compounds: role of peroxisome proliferator-activated receptors activation.

Platelets are crucial mediators of the acute complications of atherosclerosis causing life-threatening ischemic events throughout plaque development. The inhibition of the platelet function has been used for a long time in an effort to prevent and treat cardiovascular diseases. However, morbidity and mortality figures indicate that current anti-platelet strategies are far from a panacea. In this context, a large number of natural bioactive compounds (NBCs) (polyphenols, terpenoids, alkaloids and fatty acids, among others) have been reported with apparent inhibitory activity on human platelets and each constituent may possess multiple targets. In this sense, the article describes how the mechanism of anti-platelet action by NBCs peroxisome proliferator-activated receptors agonists is mediated by inhibition of protein kinase-α, cyclooxygenase-1, thromboxane A2, cytosolic calcium, and indirect stimulation of protein kinase A (increased in cyclic adenosine monophosphate levels) and protein kinase G (increased in cyclic guanosine monophosphate levels).

Influência do treinamento físico aeróbio no transporte mitocondrial de ácidos graxos de cadeia longa no músculo esquelético: papel do complexo carnitina palmitoil transferase / Influence of aerobic physical training in the motochondrial transport of long chain fatty acids in the skeletal muscle: role of the carnitine palmitoil transferase

O ácido graxo (AG) é uma importante fonte de energia para o músculo esquelético. Durante o exercício sua mobilização é aumentada para suprir as necessidades da musculatura ativa. Acredita-se que diversos pontos de regulação atuem no controle da oxidação dos AG, sendo o principal a atividade do complexo carnitina palmitoil transferase (CPT), entre os quais três componentes estão envolvidos: a CPT I, a CPT II e carnitina acilcarnitina translocase. A função da CPT I durante o exercício físico é controlar a entrada de AG para o interior da mitocôndria, para posterior oxidação do AG e produção de energia. Em resposta ao treinamento físico há um aumento na atividade e expressão da CPT I no músculo esquelético. Devido sua grande importância no metabolismo de lipídios, os mecanismos que controlam sua atividade e sua expressão gênica são revisados no presente estudo. Reguladores da expressão gênica de proteínas envolvidas no metabolismo de lipídios no músculo esquelético, os receptores ativados por proliferadores de peroxissomas (PPAR) alfa e beta, são discutidos com um enfoque na resposta ao treinamento físico.

Fatty acids are an important source of energy for the skeletal muscle. During exercise, their mobilization is increased to supply the muscle energetic needs. Many points of regulation act in the fatty acids metabolism, where the carnitine palmytoiltransferase (CPT) complex is the main control system. Three compounds named CPT I, CPT II and carnitine acyl carnitine translocase (CACT) are components of this system. Its function is to control the influx of fatty acids inside the mitochondria for posterior oxidation and energy production. There is a pronounced increase in both activity and gene expression of CPT I in the skeletal muscle in response to exercise. Due to its importance in lipid metabolism, the controlling mechanisms are reviewed in the present study. The modulation of gene expression by peroxisome proliferator-activated receptors (PPARs) alpha and beta during the physical training is also discussed in this review.