PPARγ Pathway Research Articles

S-Petasin isolated from Petasites japonicus exerts anti-adipogenic activity in the 3T3-L1 cell line by inhibiting PPAR-γ pathway signaling.

Petasites japonicus is an edible and medicinal plant with a good flavor, and it is a rich source of bioactive compounds. S-Petasin has been isolated from Petasites hybridus (L.), Petasites officinalis (L.) and Petasites formosanus, but not from Petasites japonicus. In this study, we found that hexane extracts of Petasites japonicus inhibited adipogenesis in 3T3-L1 cells. After this we isolated s-petasin from Petasites japonicus. Subsequently, the 3T3-L1 pre-adipocytes were used to test whether s-petasin exerts an anti-adipogenic effect. The results showed that s-petasin presented strong anti-adipogenic activity. Further studies illustrated that s-petasin reduced glucose uptake. Moreover, results showed that triglyceride accumulation was inhibited by s-petasin in differentiated 3T3-L1 cells. Western blot assay indicated that s-petasin down-regulated the expression of PPAR-γ and its target genes in a dose dependent manner. In conclusion, we isolated s-petasin from Petasites japonicus and found that it exerted anti-adipogenic activity against 3T3-L1 cell differentiation through inhibition of the expression of PPAR-γ pathway signaling.

An insoluble polysaccharide from the sclerotium of Poria cocos improves hyperglycemia, hyperlipidemia and hepatic steatosis in ob/ob mice via modulation of gut microbiota

Metabolic syndrome characterized by obesity, hyperglycemia and liver steatosis is becoming prevalent all over the world. Herein, a water insoluble polysaccharide (WIP) was isolated and identified from the sclerotium of Poria cocos, a widely used Traditional Chinese Medicine. WIP was confirmed to be a (1-3)-β-D-glucan with an average Mw of 4.486 × 106 Da by NMR and SEC-RI-MALLS analyses. Furthermore, oral treatment with WIP from P. cocos significantly improved glucose and lipid metabolism and alleviated hepatic steatosis in ob/ob mice. 16S DNA sequencing analysis of cecum content from WIP-treated mice indicated the increase of butyrate-producing bacteria Lachnospiracea, Clostridium. It was also observed that WIP treatment elevated the level of butyrate in gut, improved the gut mucosal integrity and activated the intestinal PPAR-γ pathway. Fecal transplantation experiments definitely confirmed the causative role of gut microbiota in mediating the benefits of WIP. It is the first report that the water insoluble polysaccharide from the sclerotium of P. cocos modulates gut microbiota to improve hyperglycemia and hyperlipidemia. Thereby, WIP from P. cocos, as a prebiotic, has the potential for the prevention or cure of metabolic diseases and may elucidate new mechanism for the efficacies of this traditional herbal medicine on the regulation of lipid and glucose metabolism.

Melatonin Attenuates Acute Pancreatitis-Induced Liver Damage Through Akt-Dependent PPAR-γ Pathway

BackgroundDespite melatonin treatment diminishes inflammatory mediator production and improves organ injury after acute pancreatitis (AP), the mechanisms remain unknown. This study explores whether melatonin improves liver damage after AP through protein kinase B (Akt)-dependent peroxisome proliferator activated receptor (PPAR)-γ pathway. MethodsMale Sprague–Dawley rats were subjected to cerulein-induced AP. Animals were treated with vehicle, melatonin, and melatonin plus phosphoinositide 3-kinase (PI3K)/Akt inhibitor wortmannin 1 h following the onset of AP. Various indicators and targeted proteins were checked at 8 h in the sham and AP groups. ResultsAt 8 h after AP, serum alanine aminotransferase/aspartate aminotransferase levels, histopathology score of hepatic injury, liver myeloperoxidase activity, and proinflammatory cytokine production were significantly increased and liver tissue adenosine triphosphate concentration was lower compared with shams. AP resulted in a marked decrease in liver Akt phosphorylation and PPAR-γ expression in comparison with the shams (relative density, 0.442 ± 0.037 versus. 1.098 ± 0.069 and 0.390 ± 0.041 versus ± 1.080 0.063, respectively). Melatonin normalized AP-induced reduction in liver tissue Akt activation (1.098 ± 0.054) and PPAR-γ expression (1.145 ± 0.083) as well as attenuated the increase in liver injury markers and proinflammatory mediator levels, which was abolished by coadministration of wortmannin. ConclusionsCollectively, our findings suggest that melatonin improves AP-induced liver damage in rats, at least in part, via Akt-dependent PPAR-γ pathway.

Rosiglitazone up-regulates glial fibrillary acidic protein via HB-EGF secreted from astrocytes and neurons through PPARγ pathway and reduces apoptosis in high-fat diet-fed mice.

The anti-diabetic drug and peroxisome proliferator-activated receptor-gamma (PPARγ) agonist, rosiglitazone, alters astrocyte activation; however, its mechanism remains less-known. We hypothesized participation of epidermal growth factor receptor (EGFR), known to control astrocyte reactivity. We first detected that rosiglitazone promoted glial fibrillary acidic protein (GFAP) expression in primary astrocytes as well as the mouse cerebral cortex, associated with increased EGFR activation. Screening for EGFR ligands revealed a rosiglitazone-mediated increase of heparin-binding epidermal growth factor (HB-EGF) in astrocytes, resulting in HB-EGF release into culture medium and mouse cerebrospinal fluid too. Treatment with HB-EGF-siRNA and EGFR inhibitors showed that the rosiglitazone-induced HB-EGF and p-EFGR were interdependent, which participated in GFAP increase. Interestingly, we observed that rosiglitazone could induce cellular and secreted-HB-EGF in neurons also, contributing toward the activated EGFR-induced GFAP in astrocytes. Probing whether these effects of rosiglitazone were PPARγ-linked, revealed potential PPARγ-responsive elements within HB-EGF gene. Moreover, gel-shift, site-directed mutagenesis, chromatin-immunoprecipitation and luciferase-reporter assays demonstrated a PPARγ-dependent HB-EGF transactivation. Subsequently, we examined effects of rosiglitazone in a high-fat diet-fed diabetes mouse model, and supporting observations in the normal cortical cells, identified a rosiglitazone-induced GFAP, astrocyte and neuronal HB-EGF and secreted-HB-EGF in the cerebral cortex of diabetic mice. Moreover, assessing relevance of increased HB-EGF and GFAP revealed an anti-apoptotic role of rosiglitazone in the cerebral cortex, supported by a GFAP-siRNA as well as HB-EGF-siRNA-mediated increase in cleaved-caspase 3 and 9 levels in the rosiglitazone-treated astrocyte-neuron coculture. Overall, our study indicates that rosiglitazone may protect the brain, via a PPARγ-dependent HB-EGF/EGFR signaling and increased GFAP.

Tryptase Promotes the Profibrotic Phenotype Transfer of Atrial Fibroblasts by PAR2 and PPARγ Pathway

As shown in clinical and experimental studies, atrial fibrosis is an important mechanism for the occurrence and development of atrial fibrillation, the most common arrhythmia in the clinic with high disability and mortality. Some studies have shown the possible involvement of tryptase, a protease released by mast cells, in the fibrosis of heart tissues, but the effect and mechanism of tryptase on extracellular matrix (ECM) remodeling and atrial fibrosis is not clear yet. This study evaluated the effects of tryptase on the proliferation, migration, ECM remodeling and the balance between matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) of fibroblasts by invitro culture of atrial fibroblasts. The involvement of Protease activated receptor 2 (PAR2), platelet-derived growth factor receptor (PDGFR) or peroxisome proliferator-activated receptor (PPAR)γ were investigated with their respective antagonists. Tryptase significantly increased the cell proliferation, the protein levels of Collagen I, fibronectin and laminin, migration ability and MMP (-1, -2) levels of atrial fibroblasts in a time-dependent manner. The TIMP (-1, -2) levels of atrial fibroblasts were significantly decreased. PAR2 antagonist FSLLRY-NH2 or PPARγ antagonist GW9662 significantly abolished these profibrotic effects of tryptase. Tryptase may promote the profibrotic phenotype transfer of atrial fibroblasts by activating PAR2 and PPARγ. This finding may provide new strategies for the prevention of atrial fibrosis.

The Effect of Chinese Medicine on Lipid and Glucose Metabolism in Acute Myocardial Infarction Through PPARγ Pathway

Aim: Danqi Pill (DQP), a Chinese medicine frequently prescribed in China, has been approved to improve cardiac function by regulating cardiac energy metabolism in heart failure (HF) after acute myocardial infarction (AMI) patients. The aim of this study was to explore whether the mechanism of DQP is associated to the lipid and glucose metabolism mediated via PPARγ (peroxisome proliferator-activated receptor gamma) pathway both in vivo and in vitro.Materials and Methods: Model of HF after AMI was established with ligation of left anterior descending artery on Sprague-Dawley (SD) rats. Twenty-eight days after treatment, hematoxylin–eosin (HE) staining was applied to visualize cardiomyocyte morphological changes. High performance liquid chromatography (HPLC) was performed to assess the contents of adenosine phosphates in heart. Positron emission tomography and computed tomography (PET-CT) was conducted to evaluate the cardiac glucose metabolism. Expressions of key molecules such as PPARγ, sterol carrier protein 2 (SCP2) and long chain acyl CoA dehydrogenase (ACADL) were measured by Western blotting (WB) and immunohistochemistry (IHC). Oxygen-glucose deprivation-reperfusion (OGD/R)-induced H9C2 injury cardiomyocyte model was adopted for potential mechanism research in vitro.Results: Treatment with DQP rescued hearts from structural and functional damages as well as inflammatory infiltration. Levels of adenosine triphosphate (ATP) and energy charge (EC) in DQP group were also up-regulated compared to model group. Further results demonstrated that critical enzymes both in lipid metabolism and glucose metabolism compromised in model group compared to sham group. Intriguingly, DQP could up-regulate critical enzymes including ACADL and SCP2 in lipid metabolism accompanying with promoting effect on molecules in glycolysis simultaneously. Results on upstreaming signaling pathway demonstrated that DQP could dramatically increase the expressions of PPARγ. In vitro study suggested the efficacy of DQP could be blocked by T0070907, a selective PPARγ inhibitor.Conclusion: DQP has cardioprotective effect in improving cardiac function and energy metabolism through regulating lipid and glucose metabolism. The effects may be mediated by PPARγ pathway.

Endocrine activities and adipogenic effects of bisphenol AF and its main metabolite

Bisphenol AF (BPAF) is a fluorinated analog of bisphenol A (BPA), and it is a more potent estrogen receptor (ER) agonist. BPAF is mainly metabolized to BPAF-glucuronide (BPAF-G), which has been reported to lack ER agonist activity and is believed to be biologically inactive. The main goal of the current study was to examine the influence of the metabolism of BPAF via glucuronidation on its ER activity and adipogenesis. Also, as metabolites can have different biological activities, the effects of BPAF-G on other nuclear receptors were evaluated. First, in-vitro BPAF glucuronidation was investigated using recombinant human enzymes. Specific reporter-gene assays were used to determine BPAF and BPAF-G effects on estrogen, androgen, glucocorticoid, and thyroid receptor pathways, and on PXR, FXR, and PPARγ pathways. Their effects on lipid accumulation and differentiation were determined in murine 3T3L1 preadipocytes using Nile Red, with mRNA expression analysis of the adipogenic markers adiponectin, Fabp4, Cebpα, and PPARγ. BPAF showed strong agonistic activity for hERα and moderate antagonistic activities for androgen and thyroid receptors, and for PXR. BPAF-G was antagonistic for PXR and PPARγ. BPAF (0.1 μM) and BPAF-G (1.0 μM) induced lipid accumulation and increased expression of key adipogenic markers in murine preadipocytes. BPAF-G is therefore not an inactive metabolite of BPAF. Further toxicological and epidemiological investigations of BPAF effects on human health are warranted, to provide better understanding of the metabolic end-elimination of BPAF.

Interaction between smoking and ATG16L1T300A triggers Paneth cell defects in Crohn's disease.

It is suggested that subtyping of complex inflammatory diseases can be based on genetic susceptibility and relevant environmental exposure (G+E). We propose that using matched cellular phenotypes in human subjects and corresponding preclinical models with the same G+E combinations is useful to this end. As an example, defective Paneth cells can subtype Crohn's disease (CD) subjects; Paneth cell defects have been linked to multiple CD susceptibility genes and are associated with poor outcome. We hypothesized that CD susceptibility genes interact with cigarette smoking, a major CD environmental risk factor, to trigger Paneth cell defects. We found that both CD subjects and mice with ATG16L1T300A (T300A; a prevalent CD susceptibility allele) developed Paneth cell defects triggered by tobacco smoke. Transcriptional analysis of full-thickness ileum and Paneth cell-enriched crypt base cells showed the T300A-smoking combination altered distinct pathways, including proapoptosis, metabolic dysregulation, and selective downregulation of the PPARγ pathway. Pharmacologic intervention by either apoptosis inhibitor or PPARγ agonist rosiglitazone prevented smoking-induced crypt apoptosis and Paneth cell defects in T300A mice and mice with conditional Paneth cell-specific knockout of Atg16l1. This study demonstrates how explicit G+E can drive disease-relevant phenotype and provides rational strategies for identifying actionable targets.

Ellagic acid reveals promising anti-aging effects against d-galactose-induced aging on human neuroblastoma cell line, SH-SY5Y: A mechanistic study.

Aging is a progressive, accumulative and natural phenomenon that leads to irreversible changes in all molecules, cells, tissues and organs of an organism. Previous studies have demonstrated that d-galactose (DG) imitates human natural aging. EA has also shown many pharmacological properties including anti-inflammatory and anti-oxidant activities. In the present study, we are aimed to evaluate anti-aging effects of EA (0.01-10 μM) on DG-induced aging model in SH-SY5Y human neuroblastoma cells, using assessment of cell proliferation, lipid peroxidation (MDA), intra-cellular reactive oxygen species (ROS), inflammation (TNF-α), total glutathione content (GSH), Beta-Galactosidase (β-GAL) and advanced glycation end products (AGEs) levels. Furthermore, the effects of EA were examined on HO-1 or PPAR-γ pathways using their selective inhibitors ZnPP or GW9662, respectively. The results revealed that EA (0.01-10 μM) significantly increased cell proliferation and GSH level, while decreased the levels of ROS, MDA, TNF-α, β-GAL and AGEs following DG-induced aging. Our findings also presented that pre-incubation with ZnPP exacerbates toxicity features of DG-induced aging in all measured parameters. Furthermore, we showed that pre-incubation of EA (0.1 and 1 μM) with either GW9662 or ZnPP significantly prevents the protective activities on cell proliferation, ROS, MDA, GSH and TNF-α levels following DG-induced aging (p < 0.001 for all cases). Additionally, EA (0.1 and 1 μM) along with GW9662 did not affect the levels of β-GAL and AGES in comparison to DG-induced aging group. Although we described for the first time that EA at low concentrations (0.1-1 μM) provides greater antiaging properties than both its high concentration (10 μM) and metformin (2.5 mM) probably through PPAR-γ/HO-1 signaling pathway, but additional and deeper investigations are needed to show exact involving mechanisms. It could be suggestible that EA may be as anti-aging agent at low concentrations for age-related neurological disorders such as Parkinson's and Alzheimer's diseases.

Lipid accumulation responses in the liver of Rana nigromaculata induced by perfluorooctanoic acid (PFOA)

Perfluorooctanoic acid (PFOA) is a perfluorinated compound that is widely distributed, is persistent in the environment, and has a low-level chronic exposure effect on human health. The aim of this study was to investigate the peroxisome proliferator activated receptors γ (PPARγ) and the sterol regulatory element-binding protein 2 (SREBP2) signaling pathways in regulating the lipid damage response to PFOA in the livers of amphibians. Male and female frogs (Rana nigromaculata) were exposed to 0, 0.01, 0.1, 0.5 and 1 mg/L PFOA. After treatment, we evaluated the pathological changes in the liver by Oil Red O, staining and examined the total cholesterol (T-CHO) and triglyceride (TG) contents. The mRNA expression levels of PPARγ, Fatty acid synthase (FAS), Acetyl-CoA carboxylase (ACC), Glycerol-3-phosphate acyltransferase (GPAT), SREBP2 and 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The administration of PFOA caused marked lipid accumulation damage in the amphibian livers. The T-CHO contents were elevated significantly after PFOA treatment; these results show a dose-dependent manner in both sexes. The TG content showed a significant increase in male livers, while it was elevated significantly in female livers. The RT-PCR results showed that the mRNA expression levels of PPARγ, ACC, FAS, GPAT, SREBP2 and HMG-CoA were significantly dose-dependently increased in the PFOA-treated groups compared with those of the control group. Our results demonstrated that PFOA-induced lipid accumulation also affected the expression levels of genes FAS, ACC, GPAT and HMG-CoA in the PPARγ and SREBP2 signaling pathways in the liver. These finding will provide a scientific theoretical basis for the protection of Rana nigromaculata against PFOA effects.

Jaceosidin Inhibits Adipogenesis in 3T3-L1 Adipocytes through the PPARγ Pathway

Jaceosidin, a natural flavone, has been reported to have anti-tumorigenic, anti-oxidant, and anti-inflammatory activities. However, the anti-adipogenic effects of jaceosidin have not been investigated. In this study, we demonstrate that jaceosidin suppresses adipocyte differentiation and cellular lipid accumulation without cytotoxicity. Jaceosidin also suppresses the mRNA and protein expression of adipogenesis-related genes. To our knowledge, these results are the first evidence of the anti-adipogenic effects of jaceosidin in 3T3-L1 adipocytes and suggest the use of jaceosidin as a treatment for obesity.

GW29-e1518 Altered long non-coding RNA expression profile in rabbit atria with atrial fibrillation: TCONS_00016478 modulates atrial energy metabolic remodeling through PGC-1α/ PPARγ pathway

GW29-e1518 Altered long non-coding RNA expression profile in rabbit atria with atrial fibrillation: TCONS_00016478 modulates atrial energy metabolic remodeling through PGC-1α/ PPARγ pathway

Lipogenesis inhibition and adipogenesis regulation via PPARγ pathway in 3T3-L1 cells by Zingiber cassumunar Roxb. rhizome extracts

Zingiber cassumunar (ZC) is used by tribal people in northern Thailand in traditional remedies for anti-obesity and in food recipes. Extracts from this plant have been studied for several pharmacological effects including anti-obesity, but with no clear evidence on cellular mechanism of activity. This study aim to investigate the lipolytic and anti-adipogenic activity of crude extracts from ZC on in vitro cultures of the mouse adipocyte cell-model, 3T3-L1. Dry rhizome powder was extracted with absolute ethanol and boiled-water. On the exposed pre-adipocytes to the extracts, cytotoxicity was not detected by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Lipid content and glycerol release were assessed using Oil Red-O and a commercial Adipolysis Assay kits respectively. The extracts exhibited no significant lipolytic activity on the exposed mature-adipocytes, in serial dilutions ranging from 1 to 800 µg/ml. However, anti-lipogenic activity was presented. All extracts significantly reduced the lipid content of exposed differentiating-adipocytes. This anti-lipogenic activity was confirmed by the expression of selected genes, determined by using real-time PCR techniques, in four groups namely: adipocyte differentiation genes, glucose uptake genes, lipid metabolism genes and fatty acid oxidation genes. 1H NMR spectrum of the extracts exhibited the prominent olefinic protons of phenylbutanoids, the group of compounds previously proved with several bioactivities. This study provided evidences of mechanisms that apparently verify the traditional use of ZC to prevent obesity.

Morin Exerts Anti-Arthritic Effects by Attenuating Synovial Angiogenesis via Activation of Peroxisome Proliferator Activated Receptor-γ.

Morin, a flavonoid occurring in many dietary plants, can reduce the number of synovial blood vessels and ameliorate collagen-induced arthritis (CIA) in rats. Herein, its underlying mechanisms in view of the peroxisome proliferator activated receptor-γ (PPARγ) pathway are addressed. In vitro, wound-healing and transwell assays are conducted to explore the effect of morin on HUVECs migration. Morin inhibits HUVECs migration and tube formation induced by VEGF, which is reversed by PPARγ antagonist GW9662 or siPPARγ. Molecular docking and competitive binding assays show that morin could bind to PPARγ. Morin increases the expression of PDK4 and CD36 in a PPARγ-dependent manner and increases the luciferase activity in cells transfected with PPARγ plasmid, which indicates that morin could activate PPARγ after binding. In addition, morin increases the expression of PTEN, a target gene of PPARγ that suppresses angiogenesis and inhibits PI3K/Akt signaling. The effects of morin on the PTEN-PI3K/Akt pathway are diminished by GW9662 and siPPARγ. In vivo studies show that morin ameliorates rat CIA, reduces synovial angiogenesis, and upregulates the expression of PTEN in the synovium, which is almost completely abolished by GW9662. Morin is a potential agonist of PPARγ, which attenuates synovial angiogenesis and arthritis via the PPARγ-PTEN-PI3K/Akt pathway.

Abstract P189: The Prorenin Receptor and its Soluble From Stimulate Hepatic Triglyceride and Cholesterol Metabolism in Male Mice

Non-alcoholic fatty liver disease is strongly associated with obesity and metabolic syndrome. Our laboratory previously demonstrated that mice lacking adipose prorenin receptor (PRR) have elevated hepatic triglycerides and cholesterol contents. In addition, lack of adipose PRR induced a counter regulatory increase of hepatic PRR and plasma soluble PRR (sPRR). Therefore, our study aimed to determine whether PRR and sPRR stimulated endogenous hepatic triglycerides and cholesterol synthesis. PRR floxed male mice fed a standard diet were injected with a single dose of an adeno-associated virus thyroxine-binding globulin Cre (KO, n=5) or saline (CTL, n=6). Body weight were measured weekly for 3 weeks. The deletion of PRR in liver did not change body weight curves. Hepatic levels of TG were significantly decreased in liver PRR KO mice compared with control mice (CTL, 615 ± 196 mg/g prot; KO, 114 ± 18 mg/g prot; P=0.047). PRR KO decreased significantly PPARγ gene expression suggesting that PRR positively regulates TG contents through PPARγ pathway. Surprisingly, similar to adipose PRR KO, liver PRR KO increased significantly plasma sPRR (CTL, 5942 ± 199 pg/ml; KO, 8903 ± 559 pg/ml; P=0.001) and hepatic total cholesterol levels (CTL, 40 ± 3 mg/g prot; KO, 102 ± 6 mg/g prot; P&lt;0.0001). This elevation was associated with an increase in SREBP-2 and HMGCoA-reductase gene expression. To determine whether sPRR stimulated cholesterol synthesis, HepG2 cells were treated with sPRR and sPRR was infused in C57BL/6J mice (n=7 to 8 mice/group). Results showed that sPRR significantly up-regulated hepatic SREPB2 mRNA expression in HepG2 cells (Veh, 1.00 ± 0.04; sPRR, 1.36 ± 0.08; P=0.009) and in the liver of mice (Veh, 1.01 ± 0.07; sPRR, 1.23 ± 0.07; P=0.04). In conclusion, our results demonstrated that hepatic PRR positively regulated TG contents through a PPARγ-dependent mechanism and that sPRR stimulated cholesterol synthesis via SREBP-2 pathway. Futures studies will investigate the mechanism by which PRR and sPRR modulate lipid metabolism.

Tetrabromobisphenol-A Promotes Early Adipogenesis and Lipogenesis in 3T3-L1 Cells.

Tetrabromobisphenol A (TBBPA) is the most common flame retardant used in electrical housings, circuit boards, and automobiles. High-throughput screening and binding assays have identified TBBPA as an agonist for human peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipogenesis. TBBPA has been suggested to be an obesogen based on in vitro cellular assays and zebrafish data. We hypothesized that exposing preadipocytes to TBBPA could influence adipogenesis via genes other than those in the PPARγ pathway due to its structural similarity to bisphenol A, which demonstrates varied endocrine disrupting activities. Mouse-derived 3T3-L1 preadipocytes were induced to differentiate and continually treated with TBBPA for 8 days. High-content imaging of adipocytes displayed increased adipocyte number and lipid accumulation when treated with TBBPA. TBBPA exhibited weak induction of mPPARγ, with an AC50 of 397 µM. Quantitative PCR revealed that TBBPA exposure increased early expression of genes involved in glucocorticoid receptor (GR) signaling and PPARγ transcriptional activation, as well as upregulating downstream genes needed for adipocyte maintenance and nontraditional ER signaling, such as Gpr30. Additionally, Pref1 and Thy1, inhibitors of differentiation, were downregulated by some concentrations of TBBPA. Furthermore, proliferating preadipocytes treated with TBBPA, only prior to differentiation, exhibited increased adipocyte number and lipid accumulation after 8 days in normal culture conditions. In conclusion, TBBPA influenced gene expression changes in GR, nontraditional ER, and known adipogenic regulatory genes, prior to PPARγ expression; effects suggesting early programming of adipogenic pathways.

Rosiglitazone augments antioxidant response in the human trophoblast and prevents apoptosis†.

Insufficient perfusion of the trophoblast by maternal blood is associated with an increased generation of reactive oxygen species and complications of the placenta. In this study, we first examined whether rosiglitazone, an agonist of the peroxisome proliferator-activated receptor-γ (PPARγ), protects the human trophoblast from oxidative injury by regulating key antioxidant proteins, catalase (CAT) and the superoxide dismutases (SOD1 and SOD2). In first trimester placental explants, localization of CAT was limited to cytotrophoblasts, whereas SOD1 was expressed in both the cyto- and syncytiotrophoblasts. In first trimester placental explants, hypoxia decreased the expression of both SOD1 and SOD2, and increased apoptosis. Treatment with rosiglitazone dose-dependently upregulated anti-oxidative CAT and SOD2, and rescued hypoxic injury in first trimester villous explants and JEG-3 cells, strongly suggesting the involvement of the PPARγ in regulating their expressions. Rosiglitazone facilitated transcription activity of PPARγ, and enhanced promotor binding, increased transcriptional activity at the CAT promoter, and elevated protein expression/activity. Treatment of hypoxic JEG-3 cells with rosiglitazone resulted in mitochondrial membrane potential increase and a reduction of caspase 9 and caspase 3 activity which is consistent with improved cell survival. To complement PPARγ activation data, we also utilized the antagonist (SR-202) and siRNA to suppress PPARγ expression and demonstrate the specific role of PPARγ in reducing ROS and oxidative stress. Ex vivo examination of term human placenta revealed lower expression of antioxidant proteins in pathologic compared to healthy placental tissues, which could be rescued by rosiglitazone, indicating that rosiglitazone can improve survival of the trophoblast under pathological conditions. These findings provide evidence that the PPARγ pathway directly influences cellular antioxidants production and the pathophysiology of placental oxidative stress.

Hispidulin inhibits adipogenesis in 3T3-L1 adipocytes through PPARγ pathway

Hispidulin, a natural flavone, has been reported to have diverse pharmacological effects, including antifungal, antioxidant, and antithrombotic properties. However, an anti-adipogenic effect has not yet been reported, which is the focus of the current study. Hispidulin suppressed the differentiation of adipocytes and cellular lipid accumulation without cytotoxicity. Treatment with hispidulin at concentrations of 10, 20, and 40 μM reduced intracellular lipids by 88.1%, 81.9%, and 75.8%, respectively. In addition, hispidulin reduced mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARγ) and adiponectin. To our knowledge, these results are the first evidence of the anti-adipogenic effects of hispidulin in 3T3-L1 adipocytes, indicating that hispidulin has potential as a novel anti-obesity therapeutic.

Effects of the food additives sodium acid pyrophosphate, sodium acetate, and citric acid on hemato-immunological pathological biomarkers in rats: Relation to PPAR-α, PPAR-γ and tnfα signaling pathway

The food additives sodium acid pyrophosphate (SAPP), sodium acetate (SA), and citric acid (CA) were evaluated for their hemato-immunotoxic effects. Forty adult Sprague-Dawley rats were distributed into four groups and were orally administered water, SAPP (12.6 mg/kg), CA (180 mg/kg), or SA (13.5 mg /kg) daily for 90 days. Erythrogram and leukogram profiles were evaluated. The levels of lysozyme, nitric oxide, immunoglobulin, and phagocytic activity were measured. Histologic and immunohistochemical evaluations of splenic tissues were performed. Changes in the mRNA expression levels of peroxisome proliferator-activated receptor α and γ (PPAR-α and PPAR-γ), and tumor necrosis factor α (TNF-α) genes were assessed. A significant leukopenic condition was observed with SAPP, while CA induced marked leukocytosis, and SA showed a lymphocytosis condition. Both the innate and humoral parameters were significantly depressed. Various pathological lesions were observed, including diffuse hyperplasia of the red pulp, depletion of the white pulp, and capsular and parenchymal fibrosis. A marked decrease in CD3 T-lymphocyte and CD20 B-lymphocyte immunolabeling in rats treated with SAPP and SA was evident. Marked downregulation of PPAR-α and PPAR-γ together with upregulation of TNF-α was recorded. These results indicate that high doses of SAPP, SA and CA exert hematotoxic and immunotoxic effects with long-term exposure.

Rosiglitazone rescues human neural stem cells from amyloid-beta induced ER stress via PPARγ dependent signaling

Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a family of ligand-activated nuclear receptors known to regulate many crucial physiological and pathological conditions. Indeed, altered PPARγ transcriptional activity contributes to metabolic syndromes (obesity and hyperglycemia associated with type 2 diabetes mellitus), stroke and neurodegenerative diseases. Various studies suggest that PPARγ agonists influence neuronal deficits in Alzheimer's Disease (AD) patients and rodent models of AD. Expression of amyloid-beta (Aβ), a neuropathological marker associated with the pathogenesis of AD neuronal impairment, is inversely correlated with the activation of PPARγ-dependent neuroprotective responses. Nevertheless, molecular mechanisms by which the effects of PPARγ agonists in AD remain to be clarified. Here, we explore the PPARγ signaling pathways and networks that protect against Aβ-induced endoplasmic reticulum (ER) stress (e.g., caspase 4, Bip, CHOP, ASK1 and ER calcium), cell death (e.g., viability and cytochrome c) and mitochondrial deficiency (e.g., maximal respiratory function, COX activity, and mitochondrial membrane potential) events in the human neural stem cells (hNSCs) treated with Aβ. Co-treatment with GW9662 (an antagonist of PPARγ) effectively blocked these protective effects by rosiglitazone, providing strong evidence that PPARγ-dependent signaling rescues hNSCs from Aβ-mediated toxicity. Together, our data suggest activation of PPARγ pathway might be critical to protecting against AD-related ER stress, ER disequilibrium and mitochondrial deficiency. These findings also improve our understanding of the role of PPARγ in hNSCs, and may aid in the development and implementation of new therapeutic strategies for the treatment of AD.