Peroxisome Proliferator-activated Receptor-γ Gene Research Articles

Curcumin protects against lamotrigine-induced chronic ovarian and uterine toxicity in rats by regulating PPAR-γ and ROS production.

Lamotrigine (LTG) is an antiepileptic drug with possible adverse effects on the female reproductive system. Curcumin was declared to improve ovarian performance. Therefore, this study aimed to clarify ovulatory dysfunction (OD) associated with LTG and the role of curcumin in ameliorating this dysfunction. Adult female Wister albino rats were assigned into four groups: negative control (received saline), positive control (received curcumin only), LTG, and LTG with curcumin groups. Drugs were administered for 90 days. The hormonal profile, including testosterone, estrogen, progesterone, luteinizing hormone, and follicle-stimulating hormone, in addition to the lipid profile and glycemic analysis, were tested. Oxidative stress biomarkers analysis in the ovaries and uterus and peroxisome proliferator-activated receptor-γ (PPAR-γ) gene expression were also included. Histopathological examination of ovarian and uterine tissues and immunohistochemical studies were also performed. Curcumin could improve the OD related to chronic LTG intake. That was proved by the normalization of the hormonal profile, glycemic control, lipidemic status, oxidative stress markers, and PPAR-γ gene expression. The histopathological and immunohistochemical examination of ovarian and uterine tissues revealed an improvement after curcumin administration. The results describe an obvious deterioration in ovarian performance with LTG through the effect on lipidemic status, PPAR-γ gene, and creating an oxidative stress condition in the ovaries of chronic users, with a prominent improvement with curcumin addition to the treatment protocol.

Coconut oil based self-nano emulsifying delivery systems mitigate ulcerogenic NSAIDs side effect and enhance drug dissolution: Formula optimization, in-vitro, and in-vivo assessments

Gastric ulcer is a common gastrointestinal ailment that affects many people worldwide. NSAIDs induced ulcers are the second most common etiology of gastric ulcers. Coconut oil has well-known potential anti-ulcerogenic characteristics. This work aimed to develop and optimize diclofenac potassium (a highly used model drug of NSAIDs) as self-nanoemulsifying delivery system containing coconut oil (DFP-COSNEDS) to overcome its ulcerogenic effect. A mixture design was applied for formula optimization and investigation of the effect of different formulation factors on the droplet size (DS) and polydispersity index (PDI) of the prepared DFP-COSNEDS. The optimized formulae showed good self-emulsification characters and better drug dissolution compared with the drug suspension. The ulcer protection was assessed in-vivo using 7 groups of adult male Wistar rats. Oxidative stress parameters (MDA, GSH, and SOD), inflammatory mediators (PGE-2, TNF-α, and IL-6) and peroxisome proliferator-activated receptor-γ (PPAR-γ) gene expression were measured. The results revealed that pure coconut oil and DFP-COSNEDS containing 25 % of coconut oil showed close figures to normal group and better values than famotidine (FAM) group. In conclusion, coconut oil showed high potential for gastric-protection activity against DFP induced ulcer. DFP-COSNEDS offers dual benefits of improving DFP dissolution and alleviating its ulcerogenic effect.

Clinical characteristics and efficacy of pioglitazone in a Japanese patient with familial partial lipodystrophy due to peroxisome proliferator-activated receptor γ gene mutation.

Familial partial lipodystrophy (FPLD) 3 is a rare genetic disorder caused by peroxisome proliferator-activated receptor γ gene (PPARG) mutations. Most cases have been reported in Western patients. Here, we describe a first pedigree of FPLD 3 in Japanese. The proband was a 51-year-old woman. She was diagnosed with fatty liver at age 32 years, dyslipidemia at age 37 years, and diabetes mellitus at age 41 years. Her body mass index was 18.5 kg/m2, and body fat percentage was 19.2%. On physical examination, she had less subcutaneous fat in the upper limbs than in other sites. On magnetic resonance imaging, atrophy of subcutaneous adipose tissue was seen in the upper limbs and lower legs. Fasting serum C-peptide immunoreactivity was high (3.4 ng/mL), and the plasma glucose disappearance rate was low (2.07%/min) on an insulin tolerance test, both suggesting apparent insulin resistance. The serum total adiponectin level was low (2.3 μg/mL). Mild fatty liver was seen on abdominal computed tomography. On genetic analysis, a P495L mutation in PPARG was identified. The same mutation was also seen in her father, who had non-obese diabetes mellitus, and FPLD 3 was diagnosed. Modest increases in body fat and serum total adiponectin were seen with pioglitazone treatment. Attention should be paid to avoid overlooking lipodystrophy syndromes even in non-obese diabetic patients if they show features of insulin resistance.

Molecular Dynamics Simulation and Essential Dynamics of Deleterious Proline 12 Alanine Single-Nucleotide Polymorphism in PPARγ2 Associated with Type 2 Diabetes, Cardiovascular Disease, and Nonalcoholic Fatty Liver Disease.

Background. Peroxisome proliferator-activated receptor-γ (PPARγ) gene is located at 3p25 position. PPARγ functions as the master regulator of glucose homeostasis and lipoprotein metabolism, and recent studies have reported that it is involved in various metabolic diseases such as diabetes mellitus, hyperlipidemia, coronary artery disease (CAD), and nonalcoholic fatty liver disease (NAFLD). PPARγ1 and PPARγ2 are necessary for the development of adipose tissue and insulin sensitivity regulation. But PPARγ2 is the isoform that was controlled in response to nutrient intake and obesity. Methodology. In this study, we used computational techniques to show the impact of Pro12Ala polymorphism on PPARγ2. The 3-D structure of PPARγ2 was modeled using I-TASSER server. The modeled structure was validated with the ZLab server, and the mutation was created with SPDB viewer. Stability prediction tools were used. Molecular dynamics simulation (MDS) was used to understand the structural and functional behavior of the wild type and mutant. Essential dynamics was also applied. Results and Conclusions. Stability prediction tools were showed that this mutation has a destabilizing effect on the PPARγ2 structure. The RMSD, RMSF, Rg, SASA, and DSSP were in line with H-bond results that showed less flexibility in the mutant structure. Essential dynamics was used to verify MDS results. Pro12Ala polymorphism leads to rigidity of the PPARγ2 protein and might disturb the conformational changes and interactions of PPARγ2 and results in type 2 diabetes mellitus (T2DM), CAD, and NAFLD. This study can help scientists to develop a drug therapy against these diseases.

Challenges in Managing Metabolic Complications in a Patient With Familial Partial Lipodystrophy Type 3

Familial partial lipodystrophy (FPL) is a rare group of autosomal dominant genetic disorders which causes variable loss of subcutaneous fat from abdomen, thorax or extremities in addition to the numerous metabolic complications like insulin resistance, diabetes mellitus and dyslipidemia1. FPL type 3 was first characterized by Agarwal et al. in 20021, in which peroxisome proliferator-activated receptor-γ (PPARγ) gene was the molecular basis of this disorder. It is extremely rare and so far only 30 patients or so have been recognized with this mutation2. FPL3 is unique because it generally spares the loss of fat from trunk, face and neck region and also presents with more severe metabolic derangements. We report a case of a young female with PPARγ mutation leading to numerous metabolic complications. A 19 year old female with FPL3 was seen by adult endocrinology as a transition from pediatric endocrinology. She was found to have hypertriglyceridemia on routine labs done at the age of 11. Patient reported loss of subcutaneous fat from her extremities and eruptive xanthoma on flexor surfaces at the time of diagnosis along with a positive family history of hypertriglyceridemia induced pancreatitis and Myocardial infarction at the age of 40 in her father. Her triglyceride level has varied between 600 and 3000 (normal 20–149 mg/dl) over the years. FPL3 was diagnosed based on genetic testing. She was prescribed fenofibrate and fish oil, and statin was added thereafter. She developed type 2 diabetes and was started on metformin and pioglitazone. She was noted to have hypertension and was treated with amlodipine and lisinopril. She also was found to have Polycystic Ovarian Syndrome (PCOS) based on menstrual irregularities, hirsutism and ultrasound showing multiple ovarian cysts, and was treated with spironolactone. Her most recent labs show triglyceride level of 2400 mg/dl and HbA1c of 8.3. PPARγ gene mutation in FPL3 leads to insulin resistance and hence patients often develop hypertriglyceridemia, type 2 diabetes, PCOS and hypertension. In terms of treatment options, we are still limited to pioglitazone, metformin, statins and fish oil. Often these are not sufficient in addressing the complexity of metabolic derangements in these patients who have an increased risk of cardiovascular events at a young age. Further research about agents targeting this gene in particular would be beneficial. 1. Agarwal et al. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab. 2002 Jan; 87(1):408–411. 2. Garg A. Lipodystrophies: Genetic and Acquired Body Fat Disorders. J Clin Endocrinol Metab. 2011;96(11): 3313–3325.

Diet and PPARG2 Pro12Ala Polymorphism Interactions in Relation to Cancer Risk: A Systematic Review.

Peroxisome proliferator-activated receptor-γ2 gene Pro12Ala allele polymorphism (PPARG2 Pro12Ala; rs1801282) has been linked to both cancer risk and dietary factors. We conducted the first systematic literature review of studies published before December 2020 using the PubMed database to summarize the current evidence on whether dietary factors for cancer may differ by individuals carrying C (common) and/or G (minor) alleles of the PPARG2 Pro12Ala allele polymorphism. The inclusion criteria were observational studies that investigated the association between food or nutrient consumption and risk of incident cancer stratified by PPARG2 Pro12Ala allele polymorphism. From 3815 identified abstracts, nine articles (18,268 participants and 4780 cancer cases) covering three cancer sites (i.e., colon/rectum, prostate, and breast) were included. CG/GG allele carriers were more impacted by dietary factors than CC allele carriers. High levels of protective factors (e.g., carotenoids and prudent dietary patterns) were associated with a lower cancer risk, and high levels of risk factors (e.g., alcohol and refined grains) were associated with a higher cancer risk. In contrast, both CG/GG and CC allele carriers were similarly impacted by dietary fats, well-known PPAR-γ agonists. These findings highlight the complex relation between PPARG2 Pro12Ala allele polymorphism, dietary factors, and cancer risk, which warrant further investigation.

Falcarindiol Purified From Carrots Leads to Elevated Levels of Lipid Droplets and Upregulation of Peroxisome Proliferator-Activated Receptor-γ Gene Expression in Cellular Models.

Falcarindiol (FaDOH) is a cytotoxic and anti-inflammatory polyacetylenic oxylipin found in food plants of the carrot family (Apiaceae). FaDOH has been shown to activate PPARγ and to increase the expression of the cholesterol transporter ABCA1 in cells, both of which play an important role in lipid metabolism. Thus, a common mechanism of action of the anticancer and antidiabetic properties of FaDOH may be due to a possible effect on lipid metabolism. In this study, the effect of sub-toxic concentration (5 μM) of FaDOH inside human mesenchymal stem cells (hMSCs) was studied using white light microscopy and Raman imaging. Our results show that FaDOH increases lipid content in the hMSCs cells as well as the number of lipid droplets (LDs) and that this can be explained by increased expression of PPARγ2 as shown in human colon adenocarcinoma cells. Activation of PPARγ can lead to increased expression of ABCA1. We demonstrate that ABCA1 is upregulated in colorectal neoplastic rat tissue, which indicates a possible role of this transporter in the redistribution of lipids and increased formation of LDs in cancer cells that may lead to endoplasmic reticulum stress and cancer cell death.

FADS and PPARG2 Single Nucleotide Polymorphisms are Associated with Plasma Lipids in 9-Mo-Old Infants

Dietary intake of polyunsaturated fatty acids (PUFAs), e.g., linoleic acid and n-3 (ω-3) long-chain PUFAs, has been shown in adults to affect plasma cholesterol and triglycerides (TGs), respectively. Little is known about the effects of PUFAs on plasma lipids in early life. The aim of this study was to explore the associations between plasma concentrations of total, LDL, and HDL cholesterol and TGs in infants and 2 single nucleotide polymorphisms (SNPs) in the fatty acid desaturase genes (FADS) oppositely associated with docosahexaenoic acid (rs1535 and rs174448) and potential effect modification by a functional peroxisome proliferator-activated receptor-γ2 gene variant (PPARG2 Pro12Ala). In 9-mo-old infants (n=561) from 3 Danish cohorts, we analyzed associations between plasma lipids, erythrocyte PUFAs, and FADS SNPs, and interactions with PPARG2 Pro12Ala genotype, by multiple linear regression. We also examined potential effect modification by breastfeeding, as 46% of the infants were still being breastfed. Minor allele carriage of rs174448 was associated with lower total cholesterol (difference: -0.22 mmol/L; 95% CI: -0.37, -0.06 mmol/L; P=0.006) and LDL cholesterol (difference: -0.15 mmol/L; 95% CI: -0.29, -0.01 mmol/L; P=0.035), but no associations were observed with TGs or for rs1535. Minor allele carriage of both FADS SNPs was associated with 1 SD lower HDL cholesterol, but only in currently breastfed infants (rs174448×breastfeeding, P=0.080; rs1535×breastfeeding, P=0.030) and PPARG2 minor allele carriers (rs174448×PPARG2, P=0.001; rs1535×PPARG2, P=0.004). Erythrocyte arachidonic acid and eicosapentaenoic acid were inversely associated with LDL cholesterol [estimated effect (β): -0.3 mmol/L; 95% CI: -0.06, -0.00 mmol/L per percentage of fatty acids (FA%); P=0.035] and TGs (β: -0.23 mmol/L; 95% CI: -0.41, -0.05 mmol/L per FA%; P=0.015), respectively. The observed associations with FADS variants indicate that PUFAs are involved in plasma lipid regulation in 9-mo-old infants. Observed FADS SNP differences and interactions with breastfeeding and PPARG2 warrant additional studies to explore the effects of individual FADS SNPs on PUFA status and potential genetic modification of dietary PUFA effects.

Peroxisome Proliferator-Activated Receptor-γ Gene Polymorphism in Psoriasis and Its Relation to Obesity, Metabolic Syndrome, and Narrowband Ultraviolet B Response: A Case-Control Study in Egyptian Patients.

Background:Psoriasis is a common dermatologic disease with multifactorial etiology in which genetic factors play a major role. Peroxisome proliferator-activated receptor (PPAR)-γ is expressed in keratinocytes and is known to affect cell maturation and differentiation in addition to its role in inflammation.Aim:To study the association between PPAR-γ gene polymorphism and psoriasis vulgaris in Egyptian patients to explore if this polymorphism influenced disease risk or clinical presentation.Methods:Forty-five patients with psoriasis vulgaris and 45 age, sex and body mass index matched healthy volunteers who have no present, past or family history of psoriasis as a control group were enrolled. Selected cases included obese and nonobese participants. Detection of PPAR-γ gene polymorphism was done with restriction fragment length polymorphism polymerase chain reaction. Narrow-band ultraviolet B (NBUVB) was given for every case three times/week for 12 weeks.Results:Homopolymorphism, heteropolymorphism, and Ala allele were significantly associated with cases (P = 0.01, P = 0.01, and P = 0.004, respectively) and increased risk of occurrence of psoriasis by 5.25, 3.65, and 3.37 folds, respectively. Heteropolymorphism was significantly associated with nonobese cases compared to obese ones (P = 0.01). Ala allele was significantly associated with obese cases (P = 0.001) and increased risk of occurrence of psoriasis in obese participants by 1.14 folds. Homopolymorphism, heteropolymorphism, and Ala allele were more prevalent among obese cases without metabolic syndrome (MS) than obese cases with MS but without statistical significance. Percentage of decrease of mean Psoriasis Area and Severity Index score before and after 3 months of treatment with NBUVB was higher in cases with heteropolymorphism with no significant difference between homo- and heteropolymorphism.Conclusion:PPAR-γ gene polymorphism is associated with and increased the risk of psoriasis and its associated obesity in Egyptian patients. It has no role in NBUVB response in those patients. Future large-scale studies on different populations are recommended.

Clinical relevance of peroxisome proliferator-activated receptor-γ gene polymorphisms with sepsis.

Peroxisome proliferator-activated receptor-γ (PPARγ) is a regulator of inflammation. This study aimed to explore associations between PPARγ gene single-nucleotide polymorphisms (SNPs) and susceptibility to and clinical outcome of sepsis in the North China Han population. This study included 303 patients with sepsis and 303 controls. We conducted genetic typing for 13 common PPARγ gene SNPs (improved multiplex ligation detection reaction), linkage disequilibrium mapping, and haplotype inference. Associations between SNP genotypes/haplotypes and sepsis susceptibility and outcome (septic shock, organ dysfunction, or death) were assessed using unconditional logistic regression analysis. For rs2972164, patients with genotypes CT/CT+TT had higher risk of sepsis than genotype CC (odds ratio [95% CI]: 1.74 [1.05-2.86], P=.03 and 1.72 [1.06-2.80], P=.026, respectively); the T allele was associated with increased sepsis risk compared with the C allele (1.64 [1.04-2.58], P=.033). For rs1801282, genotypes CG/CG+GG had lower risk of sepsis than genotype CC (0.55 [0.33-0.92], P=.024 and 0.57 [0.35-0.95], P=.03, respectively); the G allele was associated with decreased sepsis risk compared with the C allele (0.62 [0.39-1.01], P=.055). For rs4135275, genotypes AG/AG+GG had higher risk of severe organ dysfunction (multiple organ dysfunction syndrome score >8) than genotype AA (2.66 [1.16-6.09], P=.038 and 2.21 [1.00-4.85], P=.042, respectively). Haplotype TAT (rs2972164, rs4684846, and rs17036188) was associated with increased sepsis risk (1.66 [1.03-2.67], P=.038). No mutation was correlated with septic shock or death. PPARγ gene polymorphisms may play a role in the occurrence and progression of sepsis in the North China Han population.

Peroxisome proliferator-activated receptor-γ polymorphism (rs1801282) is associated with obesity in Egyptian patients with coronary artery disease and type 2 diabetes mellitus.

ObjectivePeroxisome Proliferator-Activated Receptor-γ (PPAR-γ) gene is one of the possible genes linking diabetes mellitus (DM) with coronary artery disease (CAD). The aim of this study is to clarify whether PPAR-γ Pro12Ala polymorphism is associated with the development of CAD in type 2 diabetic patients and to evaluate PPAR-γ Pro12Ala polymorphism genetic distribution in type 2 DM (T2DM) Egyptian subjects.MethodsPPAR-γ Pro12Ala polymorphism was determined by Real-Time PCR in serum of 405 subjects classified into 4 groups; T2DM patients (n = 105), T2DM with CAD (n = 100), CAD patients (n = 100) and healthy controls (n = 100).ResultsThe PPAR-γ Pro12Ala polymorphism was associated significantly with T2DM with CAD (group2) (OR = 3, 95% CI = (1.5–6); p = 0.001). In this study, T2DM with CAD complications carrying the PPAR-γ Pro12Ala polymorphism had higher BMI than those without the PPAR-γ Pro12Ala polymorphism (p < 0.0001). CAD patients carrying PPAR-γ Pro12Ala polymorphism had considerable insulin resistance features. Plasma paraoxanase 1(PON1) level was considerably reduced among our 3 studied groups in comparison to control group (p < 0.001).ConclusionsPPAR-γ Pro12Ala polymorphism might represent a novel risk factor for CAD in T2DM.

Effect of the Pro12Ala Polymorphism of the Peroxisome Proliferator-activated Receptor γ2 Gene on Lipid Profile and Adipokines Levels in Obese Subjects.

Peroxisome proliferator-activated receptor γ (PPARγ) is a key regulator of metabolism, adipokines production and secretion. The aim of this study was to investigate the association between the PPARγ2 gene Pro12Ala polymorphism in obesity in terms of body mass index (BMI), lipid parameters, homeostasis model assessment of insulin resistance (HOMA-IR), serum lipid, leptin, adiponectin, resistin and chemerin levels. The study included 160 obese and 140 non obese subjects. The Pro12Ala polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum lipid, leptin, adiponectin, resistin and chemerin levels were measured. No association was found between the Pro12Ala polymorphism and BMI. Strikingly, in the study group, obese subjects with the AA genotype had significantly higher triglycerides (p = 0.046) and resistin (p <0.001) levels than those with the wild-type PP and heterozygous PA genotypes. Serum leptin and chemerin levels were significantly associated with Pro-12Ala poymorphism in the obese and non obese groups (p <0.01). In the obese group, subjects with the homozygous AA genotype had significantly lower adiponectin (p = 0.010) activity than the PP genotype. Our results suggest that the PPARγ2 gene Pro12Ala polymorphism has no direct association with obesity but does have significant influences on lipid profiles and adipokines levels.

Peroxisome Proliferator-Activated Receptor-γGene Expression and Its Association with Oxidative Stress in Patients with Metabolic Syndrome

Peroxisome Proliferator-Activated Receptor-γGene Expression and Its Association with Oxidative Stress in Patients with Metabolic Syndrome

Adipogenic Differentiation of Thyroid Cancer Cells Through the Pax8-PPARγ Fusion Protein Is Regulated by Thyroid Transcription Factor 1 (TTF-1)

A subset of thyroid carcinomas contains a t(2;3)(q13;p25) chromosomal translocation that fuses paired box gene 8 (PAX8) with the peroxisome proliferator-activated receptor γ gene (PPARG), resulting in expression of a PAX8-PPARγ fusion protein, PPFP. We previously generated a transgenic mouse model of PPFP thyroid carcinoma and showed that feeding the PPARγ agonist pioglitazone greatly decreased the size of the primary tumor and prevented metastatic disease in vivo The antitumor effect correlates with the fact that pioglitazone turns PPFP into a strongly PPARγ-like molecule, resulting in trans-differentiation of the thyroid cancer cells into adipocyte-like cells that lose malignant character as they become more differentiated. To further study this process, we performed cell culture experiments with thyrocytes from the PPFP mouse thyroid cancers. Our data show that pioglitazone induced cellular lipid accumulation and the expression of adipocyte marker genes in the cultured cells, and shRNA knockdown of PPFP eliminated this pioglitazone effect. In addition, we found that PPFP and thyroid transcription factor 1 (TTF-1) physically interact, and that these transcription factors bind near each other on numerous target genes. TTF-1 knockdown and overexpression studies showed that TTF-1 inhibits PPFP target gene expression and impairs adipogenic trans-differentiation. Surprisingly, pioglitazone repressed TTF-1 expression in PPFP-expressing thyrocytes. Our data indicate that TTF-1 interacts with PPFP to inhibit the pro-adipogenic response to pioglitazone, and that the ability of pioglitazone to decrease TTF-1 expression contributes to its pro-adipogenic action.

Genotype Phenotype Correlation of Genetic Polymorphism of PPAR Gamma Gene and Therapeutic Response to Pioglitazone in Type 2 Diabetes Mellitus- A Pilot Study.

Pro12Ala polymorphism is a missense mutation at codon 12 in peroxisome proliferator-activated receptor γ gene (PPARG). This polymorphism is known to be associated with increased insulin sensitivity. Pioglitazone, a thiazolidinedione, is an anti-diabetic drug which acts as an agonist at PPAR γ receptor. To determine the association between Pro12Ala polymorphism of the PPARG and variation in therapeutic response to the PPARγ agonist, pioglitazone. The study was done as a hospital based pilot project in 30 patients with type 2 diabetes mellitus, on treatment with sulfonylurea or metformin but without adequate glycaemic control. They were started on pioglitazone as add on therapy for a period of 12 weeks. The participants were categorized as responders and non-responders based on the change in HbA1C level after 12 weeks. Pro12Ala polymorphism was analysed by polymerase chain reaction-restriction fragment length polymorphism. Logistic regression analysis was done to evaluate the associations between age, baseline body weight, BMI, waist circumference, waist-hip ratio and Pro12Ala variants with the response to pioglitazone. The p-value< 0.05 was considered significant. The frequency distributions of PPAR gamma genotypes were 80% for Pro/Pro and 20% for Pro/Ala in the study population. Among the study participants, 30% were non-responders and 70% responders to pioglitazone. A significantly higher frequency of the polymorphism was detected in the responders (p=0.005) compared to non-responders group. Our study suggests that there is a potential association between Pro12Ala polymorphism and glycaemic response to pioglitazone.

Peroxisome Proliferator-Activated Receptor-γGene Expression and Its Association with Oxidative Stress in Patients with Metabolic Syndrome.

Regulation of the peroxisome proliferator-activated receptor-γ (PPAR-γ) gene plays an important role in controlling the metabolism of lipids and inflammatory processes. Therefore, it can be associated with the pathogenesis of metabolic syndrome (MetS). The purpose of this study was to determine the expression of this gene in peripheral blood mononuclear cells (PBMC) in patients with metabolic syndrome. Using real-time polymerase chain reaction (PCR), mRNA expression of PPAR-γ was found in PBMC from 37 subjects with MetS and 30 healthy controls. Serum levels of glucose and lipid profiles were measured. The total antioxidant capacity (TAC) was measured using the ferric reducing ability of plasma (FRAP) test. Malondialdehyde (MDA) was determined using a fluorimetric method. Total oxidant status (TOS) in serum was assayed according to oxidation of ferric to ferrous in the presence of methyl orange. Super oxide dismutase (SOD) activity was measured using a Randox kit. Expression of PPAR-γ gene was significantly increased in patients with MetS compared to the control subjects (p=0.002). There was no difference in serum levels of TAC, MDA and SOD between the two study groups, but a significant difference was observed in the TOS (p=0.03). Serum levels of triglycerides and glucose were significantly higher in subjects with MetS. According to the results of our study, an increase in the expression of PPAR-γ in subjects with MetS indicated a possible role of PPAR-γ in the pathogenesis of this disease.

Polymorphisms of the PPAR-γ (rs1801282) and Its Coactivator (rs8192673) Have a Minor Effect on Markers of Carotid Atherosclerosis in Patients with Type 2 Diabetes Mellitus.

Background. The present study was designed to clarify whether common single nucleotide polymorphisms (SNPs) of the Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) gene (rs1801282) and the Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 (PGC-1α) gene (rs8192673) are associated with markers of carotid and coronary atherosclerosis in Caucasians with type 2 diabetes mellitus (T2DM). Patients and Methods. 595 T2DM subjects and 200 control subjects were enrolled in the cross-sectional study. Markers of carotid atherosclerosis were assessed ultrasonographically. In 215 out of 595 subjects with T2DM, a coronary computed tomography angiography (CCTA) was performed for diagnostic purposes. Genotyping of either rs1801282 or rs8192673 was performed using KASPar assays. Results. In our study, we demonstrated an effect of the rs1801282 on markers of carotid atherosclerosis (presence of plaques) in Caucasians with T2DM in univariate and in multivariable linear regression analyses. Finally, we did not demonstrate any association between either rs1801282 or rs8192673 and markers of coronary atherosclerosis. Conclusions. In our study, we demonstrated a minor effect of the rs1801282 on markers of carotid atherosclerosis (presence of plaques) in Caucasians with T2DM. Moreover, we demonstrated a minor effect of the rs8192673 on CIMT progression in the 3.8-year follow-up in Caucasians with T2DM.

Wnt/β-Catenin Mediates AICAR Effect to Increase GATA3 Expression and Inhibit Adipogenesis

A better understanding of the mechanism and manipulation of the tightly regulated cellular differentiation process of adipogenesis may contribute to a reduction in obesity and diabetes. Multiple transcription factors and signaling pathways are involved in the regulation of adipogenesis. Here, we report that the AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) can activate AMPK in preadipocytes and thus increase the expression of GATA3, an anti-adipogenic factor. However, AICAR-increased GATA3 is mediated by the stimulation of Wnt/β-catenin signaling in preadipocytes. Mechanistically, AICAR-activated AMPK inhibits GSK3β through a phosphorylation process that stabilizes β-catenin. This stabilized β-catenin then translocates into nucleus where it interacts with T-cell factors (TCF), leading to the increased β-catenin/TCF transcriptional activity that induces GATA3 expression. In addition, AICAR also relieves the repressing effect of the C-terminal-binding protein (CtBP) co-repressor by diverting CtBP away from the β-catenin·TCF complex at the GATA3 promoter. The anti-adipogenic effect of GATA3 and AICAR is consistently attenuated by the disruption of Wnt/β-catenin signaling. Furthermore, GATA3 suppresses key adipogenic regulators by binding to the promoters of these regulators, such as the peroxisome proliferator-activated receptor-γ (PPARγ) gene, and the disruption of Wnt/β-catenin signaling reduces the GATA3 binding at the PPARγ promoter. In differentiated adipocytes, GATA3 expression inhibition is facilitated by the down-regulation of β-catenin levels, the reduction in β-catenin binding, and the increase in CtBP binding at the GATA3 promoter. Our findings shed light on the molecular mechanism of adipogenesis by suggesting that different regulation pathways and adipogenic regulators collectively modulate adipocyte differentiation through cross-talk.

Polymorphisms of the peroxisome proliferator-activated receptor-γ (rs1801282) and its coactivator-1 (rs8192673) are associated with obesity indexes in subjects with type 2 diabetes mellitus.

ᅟThe aim of this study was to clarify whether common single nucleotide polymorphisms (SNPs) of the Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) gene (rs1801282) and the Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 (PGC-1α) gene (rs8192673) are associated with obesity indexes (BMI, waist circumference) in subjects with type 2 diabetes mellitus (T2DM) in Caucasian population. The second aim was to find an association of both polymorphisms with T2DM.MethodsTwo exonic SNPs of both genes rs1801282 of the PPAR-γ gene and rs8192673 of the PGC-1α gene) were genotyped in 881 unrelated Slovene subjects (Caucasians) with T2DM and in 348 subjects without T2DM (control subjects).ResultsFemale homozygotes with the CC genotype of the rs8192673 had higher waist circumference in comparison with subjects with other genotypes. Homozygotes (females, males) with wild allele (Pro) of the rs1801282 (Pro12Ala polymorphism) had higher waist circumference in comparison with subjects with other genotypes. In the study, there were no differences in the distributions of the rs8192673 and the rs1801282 genotypes between patients with T2DM and controls. Linear regression analyses for both polymorphisms were performed and demonstrated an independent effect of the rs1801282 of the PPAR-γ on waist circumference in subjects with T2DM, whereas an independent effect on waist circumference was not demonstrated for the rs8192673 of the PGC-1α gene.ConclusionsIn a large sample of the Caucasians the rs8192673 of the PGC-1α gene and the rs1801282 of the PPAR-γ gene were associated with waist circumference in subjects with T2DM.

Effect of dietary fat source and bird’s sex on performance and peroxisome proliferator-activated receptor-γ gene expression in broiler chicks

The present study was conducted to investigate the effects of different sources and levels of dietary fat and bird’s sex on performance and gene expression of peroxisome proliferator-activated receptor-gamma (PPARγ), as an adipose differentiation and development regulatory key, in broiler chicks. One-week-old broiler chicks (840: 420 males and 420 females) were randomly allocated into a factorial arrangement of treatments including 3 different fat sources (soybean oil, yellow grease, and poultry fat), 3 different fat levels (0, 20, and 40 g/kg of diet), and 2 sex categories (male and female) based on a completely randomized design with 4 replicates of 15 birds each. In addition to performance parameters, abdominal fat tissue was collected from 6 wk-old chicks and total RNA was extracted by RNX reagent. A semi-quantitative reverse transcription PCR was performed to investigate the effects of dietary treatments on PPARγ gene expression. Results showed that dietary fat source had no effect on body weight gain (BWG); however, supplementation of 20 g/kg fat into the broiler diets improved feed conversion ratio (FCR). Male chicks had higher feed intake and BWG, as well as the better FCR values than female broilers. The highest expression of PPARγ gene was detected in the abdominal fat of birds fed on diets containing soybean oil and poultry fat, and females expressed PPARγ gene higher than males. Our findings indicated that different dietary fat sources and sex might affect the development of broiler abdominal fat by interfering in PPARγ gene expression.