Peroxysome Proliferator-activated Receptor Research Articles

Dysregulation of the Amniotic PPARγ Pathway by Phthalates: Modulation of the Anti-Inflammatory Activity of PPARγ in Human Fetal Membranes.

Phthalates are reprotoxic pollutants that are omnipresent in the environment. Detectable in amniotic fluid, these compounds (with the most concentrated being mono-2-ethylhexyl phthalate (MEHP)) are in direct contact with fetal membranes (FMs). They can lead to the premature rupture of FMs by deregulating cellular and molecular pathways, such as, for example, the nuclear transcription factor peroxysome proliferator-activated receptor gamma (PPARγ) pathway. The objective was to study the impact of MEHP on the PPARγ pathway in FMs using amnion and choriodecidua across the three trimesters of pregnancy and the amniotic epithelial AV3 cell model by analyzing (i) PPARγ expression (mRNA and proteins) using RT-qPCR and Western blot assays; (ii) cytotoxicity and cell viability following MEHP treatment by lactate dehydrogenase (LDH) measurement and using Cell-counting Kit 8; and (iii) modulation by MEHP of PPARγ transcriptional activity (using a reporter gene assay) and PPARγ anti-inflammatory properties (by measuring IL6 and IL8 levels). PPARγ is expressed in the human amnion and choriodecidua during the three trimesters of pregnancy and in amniotic cells. In the AV3 cell line, MEHP is not cytotoxic and does not reduce cell viability, but it reduces PPARγ activity, here induced by a classical agonist without influencing its expression. MEHP also reduces PPARγ’s anti-inflammatory properties. In conclusion, PPARγ signaling is dysregulated by MEHP; this paves the way for future explorations to highlight the hypothesis of phthalates as an amniotic PPARγ disruptor that can explain the premature rupture of FMs.

Hypoglycemic and hypolipidemic effects of fermented milks with added roselle (Hibiscus sabdariffa L.) extract

The present study was aimed to evaluate the physicochemical properties of fermented milk containing roselle (Hibiscus sabdariffa L.) extract at different levels (0, 0.1, 0.2 and 0.3% (w/w)). Titratable acidity (TA) and pH, bacteria counts, syneresis value, water-holding capacity (WHC) and their sensory acceptance were evaluated afterwards. The fermented milk containing 0.2% roselle extract (RFM2) was selected for investigation of hypoglycemic and hypolipidemic activity. Results showed that RFM2 decreased the fasting blood glucose (FBG) levels, glycosylated hemoglobin A1c (HbA1c), the level of liver glycogen, and increased serum insulin (INS) of diabetic model mice. Moreover, RFM2 treatment improved the body, spleen, pancreas, liver and kidney weights of diabetic mice to different degrees. After four weeks, TC concentrations in diabetic mice treated by metformin (DM), control fermented milk (CFM) and RFM2 (RFM) group was decreased by 52.52%, 43.56%, 49.10%, respectively, compare to diabetic control (DC) group, TG concentration was decreased by 52.61%, 26.49%, 33.96%, respectively. LDL-C concentration was decreased by 63.97%, 46.32%, 55.88%, respectively. And the level of HDL-C in DM, CFM, RFM group was increased by 49.12%, 37.72%, 42.11%, respectively. The FFA levels of DM, CFM and RFM group was decreased by 60.05%, 19.94%, 34.08%, respectively, compared to DC group. After diabetic mice fed with metformin, CFM and RFM2, compared with DC group, the expression of adenosine monophosphate-activated protein kinase (AMPK) in the liver was increased by 50.29%, 16.93%, 41.69%, while the expression of glucose-6-phosphatase (G6P) was downregulated which decreased by 15.42%, 6.47%, 12.44%, respectively. The expression of AMPK and glucose transporter 4 (Glut4) in skeletal muscle was increased in DM, CFM and RFM groups, which was increased by 70.86%, 28.64%, 51.73% and 58.42%, 45.18%, 48.07%, respectively. The expression of peroxysome proliferator-activated receptor (PPAR-γ) in adipose tissue was increased by 5.80%, 12.63%, 28.67%, respectively. In general, roselle extract addition could promote hypoglycemic and hypolipidemic effects of fermented milk.

Hypoglycemic and hypolipidemic effects of a polysaccharide from Lachnum YM240 and its derivatives in mice, induced by a high fat diet and low dose STZ.

Carboxymethylated and sulfated polysaccharides (CLEP and SLEP) were prepared from an exopolysaccharide previously obtained from Lachnum YM240 (LEP) by chemical modifications. Two doses (50 mg kg-1 and 200 mg kg-1 b. w.) of LEP, CLEP and SLEP were orally administered to normal mice and type 2 diabetic mice (T2DM) that were induced by streptozotocin (STZ) and a high fat diet, respectively. The hypoglycemic effect was evaluated by testing the oral glucose tolerance, fasting blood glucose (FBG) levels, fasting serum insulin (FINS), glycosylated hemoglobin A1c (HbA1c), and the hypolipidemic effect was evaluated by the body, spleen, pancreas, liver and kidney weights, as well as serum triglycerides (TG), cholesterol (TC) and free fatty acids (FFA). After four weeks of administration, LEP, CLEP and SLEP showed a marked FBG fall rate of 11.2%, 44.0% and 42.5% for the high-dose and 7.43%, 38.5% and 33.1% for the low-dose, respectively, as compared to the DC group. Moreover, compared with DC mice, TC concentrations in the high-dose groups of LEP, CLEP and SLEP were significantly decreased by 29.6%, 38.7% (P < 0.05), 33.0% (P < 0.05), and TG concentrations decreased by 18.9%, 43.9% (P < 0.01), 29.0% (P < 0.05), respectively. In addition, LEP and the derivatives significantly upregulated the expression of glucokinase (GK) and adenosine monophosphate-activated protein kinase (AMPK) in the liver, AMPK and glucose transporter 4 (Glut4) in skeletal muscle and peroxysome proliferator-activated receptor (PPAR-γ) in adipose tissue, whereas downregulated the expression of glucose-6-phosphatase (G6P) in the liver; these were examined using ELISA detection kits. These results for FBG and serum lipids indicate that LEP and its derivatives possess significant hypoglycemic and hypolipidemic effects and carboxymethylation improved the hypoglycemic and hypolipidemic effects more effectively than sulfation. Therefore, the carboxymethylated and sulfated modifications were effective ways to enhance the hypoglycemic and hypolipidemic activities of polysaccharides.

Supplementation of grazing beef cows during gestation as a strategy to improve skeletal muscle development of the offspring

The appropriate supply of nutrients in pregnant cows has been associated with the optimal development of foetal tissues, performance of their progeny and their meat quality. The aim of this study was to evaluate supplementation effects of grazing cows in different stages of gestation on skeletal muscle development and performance of the progeny. Thereby, 27 Nellore cows were divided into three groups (n=9 for each group) and their progeny as follows: UNS, unsupplemented during gestation; MID, supplemented from 30 to 180 days of gestation; LATE, supplemented from 181 to 281 days of gestation. The percentage composition of the supplement provided for the matrices was the following: ground corn (26.25%), wheat bran (26.25%) and soya bean meal (47.5%). The supplement was formulated to contain 30% CP. Supplemented matrices received 150 kg of supplement (1 and 1.5 kg/day for cows in the MID and LATE groups, respectively). After birth, a biopsy was performed to obtain samples of skeletal muscle tissue from calves to determine number and size of muscle fibres and for messenger RNA (mRNA) expression analysis. The percentage composition of the supplement provided for the progeny was the following: ground corn grain (30%), wheat bran (30%), soya bean meal (35%) and molasses (5%). The supplement was formulated to contain 25% CP and offered in an amount of 6 g/kg BW. Performance of the progeny was monitored throughout the suckling period. Means were submitted to ANOVA and regression, and UNS, MID and LATE periods of supplementation were compared. Differences were considered at P<0.10. Birth weight, average daily gain and weaning weight of the offspring did not differ among treatments (P>0.10). Similarly, no differences were observed between calves for nutrient intake (P>0.10). However, greater subcutaneous fat thickness (P=0.006) was observed in the calves of LATE group. The ribeye area (P=0.077) was greater in calves born from supplemented compared with UNS cows. The supplementation of pregnant cows did not affect the muscle fibre size of their progeny (P=0.208). On the other hand, calves born from dams supplemented at mid-gestation had greater muscle fibre number (P=0.093) compared with calves from UNS group. Greater mRNA expression of peroxysome proliferator-activated receptor α (P=0.073) and fibroblast growth factor 2 (P=0.003) was observed in the calves born from MID cows. Although strategic supplementation did not affect the BW of offspring, it did cause changes in carcass traits, number of myofibres, and mRNA expression of a muscle hypertrophy and lipid oxidation markers in skeletal muscle of the offspring.

Antidiabetic effect of total saponins from Polygonatum kingianum in streptozotocin-induced daibetic rats

BackgroundPolygonatum kingianum has been used in the prevention and treatment of diabetes, hyperlipidemia and related metabolic syndrome in Asian counties for centuries. In this study, the blood glucose regulation activity and mechanism of total saponins from P. kingianum (TSPK) were investigated in streptozotocin (STZ)-induced diabetic rats in this research. MethodsTSPK (0.025g/kg and 0.1mg/kg) was administrated by gavage to STZ-induced diabetic rats for 8 weeks. Changes of body weight, food intakes, blood glucose, serum insulin and lipid indexes were observed. Genome-wide expression profiling was applied to explore the gene expression alternation after treated with TSPK. Expressions of adenosine monophosphate activated protein kinase (AMPK), phosphoenolpyruvate carboxykinase (PEPCK), the relative transcript level of glucose kinase and glucose-6-phosphatase (GK/G6P) in the liver were investigated. Meanwhile, contents of AMPK, and glucose transporter subtype-4 (GLUT4) in skeletal muscle, and peroxysome proliferator-activated receptor (PPAR-γ) in adipose tissue were investigated. ResultsTSPK could effectively alleviate hyperglycemia and hyperlipidemia in diabetic rats. Genome-wide expression profiling showed that TSPK up-regulated the expression of GLUT4 while down-regulated the expression of G6P in insulin signal pathway. In the liver, the expression of AMPK and GK are increased. Further more, TSPK promoted the expressions of GLUT4 in skeletal muscle, and PPAR-γ in adipose tissue, respectively. ConclusionThese results provide possible mechanisms for the antidiabetic effects of TSPK. TSPK could promote not only glycogenesis but also glucose utilization in peripheral tissue. Our results suggested that TSPK may be used as adjuvant therapy to control blood glucose and insulin resistance in type 2 diabetic individuals.

Activation of the prostaglandin D2 metabolic pathway in Crohn's disease: involvement of the enteric nervous system.

BackgroundRecent works provide evidence of the importance of the prostaglandin D2 (PGD2) metabolic pathway in inflammatory bowel diseases. We investigated the expression of PGD2 metabolic pathway actors in Crohn’s disease (CD) and the ability of the enteric nervous system (ENS) to produce PGD2 in inflammatory conditions.MethodsExpression of key actors involved in the PGD2 metabolic pathway and its receptors was analyzed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in colonic mucosal biopsies of patients from three groups: controls, quiescent and active CD patients. To determine the ability of the ENS to secrete PGD2 in proinflammatory conditions, Lipocalin-type prostaglandin D synthase (L-PGDS) expression by neurons and glial cells was analyzed by immunostaining. PGD2 levels were determined in a medium of primary culture of ENS and neuro-glial coculture model treated by lipopolysaccharide (LPS).ResultsIn patients with active CD, inflamed colonic mucosa showed significantly higher COX2 and L-PGDS mRNA expression, and significantly higher PGD2 levels than healthy colonic mucosa. On the contrary, peroxysome proliferator-activated receptor Gamma (PPARG) expression was reduced in inflamed colonic mucosa of CD patients with active disease. Immunostaining showed that L-PGDS was expressed in the neurons of human myenteric and submucosal plexi. A rat ENS primary culture model confirmed this expression. PGD2 levels were significantly increased on primary culture of ENS treated with LPS. This production was abolished by AT-56, a specific competitive L-PGDS inhibitor. The neuro-glial coculture model revealed that each component of the ENS, ECG and neurons, could contribute to PGD2 production.ConclusionsOur results highlight the activation of the PGD2 metabolic pathway in Crohn’s disease. This study supports the hypothesis that in Crohn’s disease, enteric neurons and glial cells form a functional unit reacting to inflammation by producing PGD2.

Reporter cell lines to evaluate the selectivity of chemicals for human and zebrafish estrogen and peroxysome proliferator activated γ receptors.

Zebrafish is increasingly used as an animal model to study the effects of environmental nuclear receptors (NRs) ligands. As most of these compounds have only been tested on human NRs, it is necessary to measure their effects on zebrafish NRs. Estrogen receptors (ER) α and β and peroxysome proliferator activated receptor (PPAR) γ are main targets of environmental disrupting compounds (EDCs). In humans there are two distinct nuclear ERs (hERα and hERβ), whereas the zebrafish genome encodes three ERs, zfERα, zfERβ1, and zfERβ2. Only one isoform of PPARγ is expressed in both humans and zebrafish. In this review, we described reporter cell lines that we established to study the interaction of EDCs with human and zebrafish ERs and PPARγ. Using these cell lines, we observed that zfERs are thermo-sensitive while zfPPARγ is not. We also showed significant differences in the ability of environmental and synthetic ligands to modulate activation of zfERs and zfPPARγ in comparison to hERs and hPPARγ. Some environmental estrogens (bisphenol A, mycoestrogens) which are hER panagonists displayed greater potency for zfERα as compared to zfERβs. hERβ selective agonists (8βVE2, DPN, phytoestrogens) also displayed zfERα selectivity. Among hERα selective synthetic agonists, 16α-LE2 was the most zfERα selective compound. Almost all zfPPARγ environmental ligands (halogenated bisphenol A derivatives, phthalates, perfluorinated compounds) displayed similar affinity for human and zebrafish PPARγ while pharmaceutical hPPARγ agonists like thiazolidones are not recognized by zfPPARγ. Altogether, our studies show that all hERs and hPPARγ ligands do not control in a similar manner the transcriptional activity of zfERs and zfPPARγ and point out that care has to be taken in transposing the results obtained using the zebrafish as a model for human physiopathology.

Inhibition of adipogenic differentiation of bone marrow mesenchymal stem cells by erythropoietin via activating ERK and P38 MAPK.

We examined whether erythropoietin (EPO) can inhibit adipogenic differentiation of mesenchymal stem cells (MSCs) in the mouse bone marrow and its underlying mechanism. We separated and extracted mouse bone marrow MSCs and induced adipogenic differen-tiation using 3-isobutyl-1-methylxanthine, insulin, and dexamethasone. Different concentrations of EPO were added to the cells and observed by Oil Red O staining on the 20th day to quantitatively analyze the degree of cell differentiation. mRNA expression levels of peroxysome proliferator-activated receptor γ (PPARγ), CCAAT enhancer binding protein α, and adiponectin were analyzed by real-time quantitative polymerase chain reaction, and the activity of PPARγ, extracellular sig-nal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (p38 MAPK) were determined by western blotting. EPO significantly inhibited adipogenic differentiation of MSCs after 20 days and reduced absorbance values by Oil Red O staining without affecting proliferation activity. EPO downregulated the mRNA expression of PPARγ, CCAAT enhancer binding protein α, fatty acid binding protein 4, and adiponec-tin during adipogenesis and increased protein phosphorylation of ERK, p38 MAPK, and PPARγ during differentiation. EPO downregulated the mRNA expression of PPARγ, CCAAT enhancer binding protein α, fatty acid binding protein 4, and adiponectin by increasing protein phosphor-ylation of ERK, p38 MAPK, and PPARγ during differentiation, which inhibited adipogenic differentiation of MSCs.

In Vitro and In Vivo Enhancement of Adipogenesis by Italian Ryegrass (Lolium multiflorum) in 3T3-L1 Cells and Mice

Adipogenesis is very much important in improving the quality of meat in animals. The aim of the present study was to investigate the in vitro and in vivo adipogenesis regulation properties of Lolium multiflorum on 3T3-L1 pre-adipocytes and mice. Chemical composition of petroleum ether extract of L. multiflorum (PET-LM) confirmed the presence of fatty acids, such as α-linolenic acid, docosahexaenoic acid, oleic acid, docosatetraenoic acid, and caprylic acid, as the major compounds. PET-LM treatment increased viability, lipid accumulation, lipolysis, cell cycle progression, and DNA synthesis in the cells. PET-LM treatment also augmented peroxysome proliferator activated receptor (PPAR)-γ2, CCAAT/enhancer binding protein-α, adiponectin, adipocyte binding protein, glucose transporter-4, fatty acid synthase, and sterol regulatory element binding protein-1 expression at mRNA and protein levels in differentiated adipocytes. In addition, mice administered with 200 mg/kg body weight PET-LM for 8 weeks showed greater body weight than control mice. These findings suggest that PET-LM facilitates adipogenesis by stimulating PPARγ-mediated signaling cascades in adipocytes which could be useful for quality meat development in animals.

1043 – Expression of obesity related genes and leptin serum levels are decreased in turkish schizophrenia patients, case-control study

Antipsychotic medications can induce metabolic abnormalities (weight gain) in schizophrenia (SCH). Leptin receptor (LEPR), leptin (LEP) and peroxysome proliferator-activated receptor g2 (PPARg2) are the potential genetic determinants which might be liable of the metabolic dysregulation. The aim of this study was to evaluate the effect of LEP c.-2548G>A, LEPR p.Q223R polymorphisms and the impact of mRNA levels of LEP, LEPR, and PPARg2 along with the serum leptin levels on metabolic adversities in SCH patients (n=132) and controls (n=114). Metabolic profiles, LEP, LEPR gene polymorphisms and the gene expressions of LEP, LEPR and PPARg2 were studied in SCH patients and controls. BMI, cholesterol and fasting glucose levels were higher in SCH patients compared to controls. LEP c.-2548 (GA+AA) genotypes were two fold lower in SCH patients versus controls (p< 0.05), and no significant difference was observed in LEPR p.Q223R genotypes. Interestingly, leptin serum levels were lower in SCH patients compared to controls (p< 0.05). Leptin, leptin receptor and PPARg2 gene expressions were found to be decreased in SCH patients compared to controls (p< 0.001, p< 0.001 and p≤0.05, respectively). Leptin receptor, leptin and PPARg2 genes could be potential risk factors in developing metabolic adversities in SCH.

Adipogenic differentiation of scaffold-bound human adipose tissue-derived stem cells (hASC) for soft tissue engineering

Adipose tissue engineering, instead of tissue substitution, often uses autologous adipose tissue-derived stem cells (hASC). These cells are known to improve graft integration and to support neovascularization of scaffolds when seeded onto biomaterials. In this study we thought to engineer adipose tissue using scaffold-bound hASC, since they can be differentiated into the adipocyte cell lineage and used for soft tissue regeneration. We show here by microscopy and gene expression of the peroxysome proliferator-activated receptor gene (PPARγ2) that hASC growing on polypropylene fibrous scaffolds as well as on three-dimensional nonwoven scaffolds can be turned into adipose tissue within 19 days. Freshly isolated hASC displayed a higher differentiation potential than hASC cultured for eight passages. In addition, we proved a modified alginate microcapsule to directly induce adipogenic differentiation of incorporated hASC. The results may help to improve long-term success of adipose tissue regeneration, especially for large-scale soft tissue defects, and support the development of cell–scaffold combinations which can be shaped individually and directly induce the adipogenic differentiation of incorporated hASC at the site of implantation.

The PPARGC1Agene Gly482Ser in Polish and Russian athletes

Peroxysome proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α; encoded by the gene PPARGC1A in humans) is a crucial component in training-induced muscle adaptation because it is a co-activator of transcriptional factors that control gene expression in coordinated response to exercise. It has been suggested that a Gly482Ser substitution in PPARGC1A has functional relevance in the context of human disorders and athletic performance. To test this hypothesis, we examined the genotype distribution of PPARGC1A Gly482Ser in a group of Polish athletes and confirmed the results obtained in a replication study of Russian athletes. We found that the 482Ser allele was under-represented in the cohort of Polish and Russian athletes examined compared with unfit controls (P < 0.0001). A statistically significant low frequency of the 482Ser allele was observed among the endurance,strength-endurance, and sprint-strength groups of Polish athletes (P = 0.019, P = 0.022, and P < 0.0001, respectively). The replication study revealed that the 482Ser allele was also less prevalent in Russian endurance and strength-endurance athletes (P = 0.029 and P < 0.0001, respectively). Our results suggest that the PPARGC1A Gly482Ser polymorphism is associated with elite endurance athletic status. These findings support the hypothesis that the PPARGC1A 482Ser allele may impair aerobic capacity: thus, the Gly482 allele may be considered a beneficial factor for endurance performance.

市販後に分かる薬の安全性と最近の撤退薬 ６．チアゾリジンジオン誘導体

A thiazolidinedione derivative, troglitazone, which binds peroxysome proliferator-activated receptor γ (PPARγ) to improve insulin resistance, was introduced into the market in 1997 as the first agent to improve insulin resistance in type2 diabetes mellitus. However, this agent caused severe hepatic dysfunction and was withdrawn from the market in 2003. Causes for severe hepatic dysfunction by troglitazone have not yet been fully understood. Based on the clinical course, the lack of eruption, fever and eosinophia hepatic dysfunction is thought to be caused not by allergic reactions but by drug idiosyncracy. It has been reported that the combined null genotype of glutathione-S-transferase (GST) theta 1 and GST mu 1 are more prevalent among patients of hepatic dysfunction caused by troglitazone than among those who showed no hepatic abnormality. Pioglitazone, another thiazolidinedione derivative on the market, has been shown not to cause hepatic failure in a large-scale postmarketing surveillance study of more than 20,000 patients. Rosiglitazone, a thiazolidinedione derivative, has been reported to increase myocardial infarction compared with other hypoglycaemic agents or placebo by meta-analyses. Both rosiglitazone and pioglitazone increase the incidence of congestive heart failure presumably by increasing sodium and water retention.

Carbon monoxide protects against ventilator-induced lung injury via PPAR-gamma and inhibition of Egr-1.

Ventilator-induced lung injury (VILI) leads to an unacceptably high mortality. In this regard, the antiinflammatory properties of inhaled carbon monoxide (CO) may provide a therapeutic option. This study explores the mechanisms of CO-dependent protection in a mouse model of VILI. Mice were ventilated (12 ml/kg, 1-8 h) with air in the absence or presence of CO (250 ppm). Airway pressures, blood pressure, and blood gases were monitored. Lung tissue was analyzed for inflammation, injury, and gene expression. Bronchoalveolar lavage fluid was analyzed for protein, cell and neutrophil counts, and cytokines. Mechanical ventilation caused significant lung injury reflected by increases in protein concentration, total cell and neutrophil counts in the bronchoalveolar lavage fluid, as well as the induction of heme oxygenase-1 and heat shock protein-70 in lung tissue. In contrast, CO application prevented lung injury during ventilation, inhibited stress-gene up-regulation, and decreased lung neutrophil infiltration. These effects were preceded by the inhibition of ventilation-induced cytokine and chemokine production. Furthermore, CO prevented the early ventilation-dependent up-regulation of early growth response-1 (Egr-1). Egr-1-deficient mice did not sustain lung injury after ventilation, relative to wild-type mice, suggesting that Egr-1 acts as a key proinflammatory regulator in VILI. Moreover, inhibition of peroxysome proliferator-activated receptor (PPAR)-gamma, an antiinflammatory nuclear regulator, by GW9662 abolished the protective effects of CO. Mechanical ventilation causes profound lung injury and inflammatory responses. CO treatment conferred protection in this model dependent on PPAR-gamma and inhibition of Egr-1.

Effects of Rosiglitazone (a Peroxysome Proliferator-Activated Receptor .GAMMA. Agonist) on the Blood Pressure and Aortic Structure in Metabolically Programmed (Perinatal Low Protein) Rats

This study investigated the effects of rosiglitazone on nutritionally programmed chronic disease, with a focus on blood pressure (BP) and aortic wall structural remodeling. Wistar pregnant rats were fed one of two diets: a normal protein diet (19% protein; NP rats) or low-protein diet (5% protein; LP rats). Male offspring at 3 months of age were randomly divided into four groups: NP offspring treated with rosiglitazone (NPR); untreated NP offspring (NP); LP offspring treated with rosiglitazone (LPR); untreated LP offspring (LP). Rosiglitazone was administered at a dose of 5 mg/kg/d until 6 months of age. BP was elevated in LP offspring. Rosiglitazone reduced BP beginning in the first week of treatment in the LPR offspring. The insulin sensitivity was increased in LP offspring, and was not altered by rosiglitazone. LP offspring exhibited a 40% reduction in the amount of elastic fibers in the aorta wall compared with NP offspring (p < 0.01), and the quantity of elastic fibers was not altered by rosiglitazone. The smooth muscle cells, elastic lamellae, circumferential wall tension (CWT) and tensile stress (TS) were increased in LP offspring, indicating increased blood flow in the aorta. Rosiglitazone reduced both CWT and TS by 30% compared to the levels in untreated LP offspring (p < 0.01 for both). Rosiglitazone restored the expressions of angiotensin II type 1 receptor and endothelial nitric oxide synthase nearly to the levels in the NP offspring. ANOVA disclosed a significant two-factor interaction between protein content in the diet and rosiglitazone treatment (p < 0.001 for CWT and p < 0.00001 for TS, two-way ANOVA). We conclude that rosiglitazone has beneficial effects in reducing the BP and the aortic tunica media hypertrophy with consequent balance of the wall stress in metabolically programmed offspring.

PPARs and Adipose Cell Plasticity

Due to the importance of fat tissues in both energy balance and in the associated disorders arising when such balance is not maintained, adipocyte differentiation has been extensively investigated in order to control and inhibit the enlargement of white adipose tissue. The ability of a cell to undergo adipocyte differentiation is one particular feature of all mesenchymal cells. Up until now, the peroxysome proliferator-activated receptor (PPAR) subtypes appear to be the keys and essential players capable of inducing and controlling adipocyte differentiation. In addition, it is now accepted that adipose cells present a broad plasticity that allows them to differentiate towards various mesodermal phenotypes. The role of PPARs in such plasticity is reviewed here, although no definite conclusion can yet be drawn. Many questions thus remain open concerning the definition of preadipocytes and the relative importance of PPARs in comparison to other master factors involved in the other mesodermal phenotypes.

SIRT1 Modulating Compounds from High-Throughput Screening as Anti-Inflammatory and Insulin-Sensitizing Agents

The nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylase SIRT1 has been linked to fatty acid metabolism via suppression of peroxysome proliferator-activated receptor gamma (PPAR-gamma) and to inflammatory processes by deacetylating the transcription factor NF-kappaB. First, modulation of SIRT1 activity affects lipid accumulation in adipocytes, which has an impact on the etiology of a variety of human metabolic diseases such as obesity and insulin-resistant diabetes. Second, activation of SIRT1 suppresses inflammation via regulation of cytokine expression. Using high-throughput screening, the authors identified compounds with SIRT1 activating and inhibiting potential. The biological activity of these SIRT1-modulating compounds was confirmed in cell-based assays using mouse adipocytes, as well as human THP-1 monocytes. SIRT1 activators were found to be potent lipolytic agents, reducing the overall lipid content of fully differentiated NIH L1 adipocytes. In addition, the same compounds have anti-inflammatory properties, as became evident by the reduction of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). In contrast, a SIRT1 inhibitory compound showed a stimulatory activity on the differentiation of adipocytes, a feature often linked to insulin sensitization.

Short-term activation of peroxysome proliferator-activated receptor β/δ increases fatty acid oxidation but does not restore insulin action in muscle cells from type 2 diabetic patients

Defective fatty acid oxidation in skeletal muscle is one of the possible causes of insulin resistance. Peroxisome proliferator-activated receptor beta activators are strong inducers of fatty acid oxidation. The aim of this study was to verify whether activation of fatty acid oxidation by PPARbeta agonists in human skeletal muscle cells prepared from type 2 diabetic patients could improve the reduced responses to insulin that characterized this cell model. GW0742 (10 nM) significantly increased fatty acid oxidation and oxidative gene expression in myotubes prepared from both healthy subjects and type 2 diabetic patients. In cells from control subjects, incubation with the agonist for 48 h affected neither insulin-induced rate of glycogen synthesis nor the phosphorylation state of protein kinase B (PKB serine 473). Myotubes from type 2 diabetic patients displayed marked reduction in the effects of insulin on glycogen synthesis and on PKB phosphorylation. However, treatment with PPARbeta agonists did not restore these defects. Therefore, these results indicate that induction of fatty acid oxidation with PPARbeta activators during short-term exposition is not sufficient to correct for insulin resistance in muscle cells from type 2 diabetic patients. This suggests that additional studies are needed to better characterize the link between fatty acid oxidation and insulin sensitivity in humans.

Pretreatment with peroxysome proliferator-activated receptor α agonist fenofibrate protects endothelium in rabbit Escherichia coli endotoxin-induced shock

To investigate the effects of fenofibrate, an activator of peroxysome proliferator activated receptor (PPAR) alpha, on vascular endothelium and on hemostasis in a rabbit endotoxic shock model. Prospective laboratory study in a university laboratory. 36 male New Zealand rabbits weighing 2.5-3 kg. We determined in vitro vascular reactivity, endothelium CD31-platelet/endothelial cell adhesion molecule (PECAM) 1 immunohistochemistry, plasma coagulation factors, and monocyte tissue factor expression 5 days after onset of endotoxic shock (0.5 mg/kg intravenous bolus, Escherichia coli lipopolysaccharide) with or without treatment by fenofibrate (mixed in the chow at a concentration of 0.5%) for 15 days before lipopolysaccharide injection and 5 days afterward. Metabolic acidosis and coagulation activation confirmed presence of shock. Fenofibrate decreased monocyte tissue factor expression. It improved endothelial-dependent relaxation at 5 days (Emax=68.2+/-3.3%, vs. 44.2+/-2.5% in the non-treated group). Endotoxin-induced deendothelialization was significantly decreased by fenofibrate at 5 days (8.5+/-1.3% vs. 19.2+/-3.1% in the nontreated group) . These data indicate for the first time that fenofibrate, an activator of PPAR-alpha, inhibits monocyte tissue factor expression and protects against endothelial dysfunction and histological injury in endotoxin-induced shock.

Un rôle pour PPARγ dans la reproduction ?

Synthetic molecules of the glitazone family are currently used in the treatment of type II diabetes. Glitazones also improve secondary pathologies that are frequently associated with insulin resistance such as the polycystic ovary syndrome (PCOS). Glitazones bind to the peroxysome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor which is highly expressed in adipose tissue. PPARgamma also binds natural ligands such as long-chain fatty acids. Recently, several groups have shown that PPARgamma is also highly expressed in ovarian granulosa cells, and that glitazones are able to modulate in vitro granulosa cell proliferation and steroidogenesis in several species. These recent data raise new questions concerning the underlying mechanism of the effect of glitazones on PCOS. One might hypothesize, as for other << glucophage >> molecules such as metformin, that it is the general improvement of glucose metabolism and insulin sensitivity by glitazones which indirectly, and via an unknown mechanism, ameliorates ovarian functionality. The data discussed here suggest now an alternative possibility, that glitazones act directly at the ovarian level. Moreover, PPARgamma also seems to play a key role in the maturation of the placenta. In particular, inactivation of PPARgamma in mice is lethal, since the foetus is unable to develop because of alterations of placental maturation. In women, the activation of PPARgamma in placenta leads to an increase of placental hormone secretion. Overall, these results raise some questions about the role of natural ligands of PPARgamma such as long chain fatty acids on female fertility and the interactions between energy metabolism and reproduction in general.