Serum Levels of the Cytokine TWEAK Are Associated with Metabolic Status in Patients with Prostate Cancer and Modulate Cancer Cell Lipid Metabolism In Vitro

Soluble TWEAK (sTWEAK) has been proposed as a prognostic biomarker of prostate cancer (PCa). We found that reduced serum levels of sTWEAK, together with higher levels of prostate-specific antigen and a higher HOMA-IR index, are independent predictors of PCa. We also showed that sTWEAK stimulus failed to alter the expression of glucose transporter genes (SLC2A4 and SLC2A1), but significantly reduced the expression of glucose metabolism-related genes (PFK, HK1 and PDK4) in PCa cells. The sTWEAK stimulation of PC-3 cells significantly increased the expression of the genes related to lipogenesis (ACACA and FASN), lipolysis (CPT1A and PNPLA2), lipid transport (FABP4 and CD36) and lipid regulation (SREBP-1 and PPARG) and increased the lipid uptake. Silencing the TWEAK receptor (Fn14) in PC-3 cells confirmed the observed lipid metabolic effects, as shown by the downregulation of ACACA, FASN, CPT1A, PNPLA2, FABP4, CD36, SREBP-1 and PPARG expression, which was paralleled by a reduction of FASN, CPT1A and FABP4 protein expression. Specific-signaling inhibitor assays show that ERK1/2 and AKT (ser473) phosphorylation can regulate lipid metabolism-related genes in PCa cells, pointing to the AKT locus as a possible target for PCa. Overall, our data support sTWEAK/Fn14 axis as a potential therapeutic target for PCa.

Maternal obesity causes fetal cardiac hypertrophy and alters adult offspring myocardial metabolism in mice

Obesity in pregnant women causes fetal cardiac dysfunction and increases offspring cardiovascular disease risk but its effect on myocardial metabolism is unknown. We hypothesised that maternal obesity alters fetal cardiac expression of metabolism-related genes and shifts offspring myocardial substrate preference from glucose towards lipids. Female mice were fed control or obesogenic diets before and during pregnancy. Fetal hearts were studied in late gestation (embryonic day, E18.5; term≈E21) and offspring were studied at 3, 6, 9 or 24 months postnatally. Maternal obesity increased heart weight and peroxisome proliferator activated receptor γ (Pparg) expression in female and male fetuses and caused left ventricular diastolic dysfunction in the adult offspring. Cardiac dysfunction progressively worsened with age in female, not male, offspring of obese dams, compared to age-matched controls. In 6-month-old offspring, exposure to maternal obesity increased cardiac palmitoyl carnitine-supported mitochondrial respiration in males and reduced myocardial 18F-fluorodeoxyglucose uptake in females. Cardiac Pparg expression remained higher in adult offspring of obese than control dams and correlated with contractile and metabolic function. Maternal obesity did not affect cardiac palmitoyl carnitine respiration in females or 18F-fluorodeoxyglucose uptake in males, or alter cardiac 3H-oleic acid uptake, pyruvate respiration, lipid content or fatty acid/glucose transporter abundance in offspring of either sex. The results support our hypothesis and show that maternal obesity affects offspring cardiac metabolism in a sex-dependent manner. Persistent upregulation of Pparg expression in response to overnutrition in utero may mechanistically underpin programmed cardiac impairments and contribute to cardiovascular disease risk in children of women with obesity.

Variation of PPARG Expression in Chemotherapy-Sensitive Patients of Hypopharyngeal Squamous Cell Carcinoma

Our previous study showed that the upregulation of peroxisome proliferator-activated receptor gamma (PPARG) could promote chemosensitivity of hypopharyngeal squamous cell carcinoma (HSCC) in chemotherapeutic treatments. Here, we acquired two more independent expression data of PPARG to validate the expression levels of PPARG in chemotherapy-sensitive patients (CSP) and its individualized variations compared to chemotherapy-non-sensitive patients (CNSP). Our results showed that overall PPARG expression was mildly downregulated ( log fold change = − 0.55 ; p value = 0.42; overexpression in three CSPs and reduced expression in four CSPs), which was not consistent with previous results ( log fold change = 0.50 ; p = 0.22 ; overexpression in nine CSPs and reduced expression in three CSPs). Both studies indicated that PPARG expression variation was significantly associated with the Tumor-Node-Metastasis (TNM) stage ( p = 7.45 e − 7 and 6.50 e − 4 , for the first and second studies, respectively), which was used as one of the predictors of chemosensitivity. The new dataset analysis revealed 51 genes with significant gene expression changes in CSPs ( LFC > 1 or <-1; p value < 0.01), and two of them (TMEM45A and RBP1) demonstrated strong coexpression with PPARG ( Pearson correlation coefficient > 0.6 or <-0.6). There were 21 significant genes in the data from the first study, with no significant association with PPARG and no overlap with the 51 genes revealed in this study. Our results support the connection between PPARG and chemosensitivity in HSCC tumor cells. However, significant PPARG variation exists in CSPs, which may be influenced by multiple factors, including the TNM stage.

Increasing Fat Deposition Via Upregulates the Transcription of Peroxisome Proliferator-Activated Receptor Gamma in Native Crossbred Chickens

This study aimed to study the role of PPARs on fat deposition in native crossbred chicken. We studied the growth, abdominal, subcutaneous, and intramuscular fat, and mRNA expression of PPARA and PPARG in adipose and muscle tissues of four chicken breeds (CH breed (100% Thai native chicken), KM1 (50% CH background), KM2 (25% CH background), and broiler (BR)). The result shows that the BR chickens had higher abdominal fat than other breeds (p < 0.05) and the KM2 had an abdominal fat percentage higher than KM1 and CH respectively (p < 0.05). The intramuscular fat of BR was greater than KM1 and CH (p < 0.05). In adipose tissue, PPARA expression was different among the chicken breeds. However, there were breed differences in PPARG expression. Study of abdominal fat PPARG expression showed the BR breed, KM1, and KM2 breed significantly greater (p < 0.05) than CH. In 8 to 12 weeks of age, the PPARG expression of the CH breed is less than (p < 0.05) KM2. Crossbreeding improved the growth of the Thai native breed, there was also a corresponding increase in carcass fatness. However, there appears to be a relationship between PPARG expression and fat deposition traits. therefore, PPARG activity hypothesized to plays a key role in lipid accumulation by up-regulation.

Association of PPARG and PPARGC1 polymorphism with effectiveness of exercise-induced fat mass loss

Aim. Peroxisome proliferator activated receptor gamma (PPARG) and PPARG coactivator 1α (PPARGC1A) is a key regulator of energy metabolism. This study examines the influence of PPARG and PPARGC1A gene polymorphisms on the PPARG expression, obesity risk, lipoprotein profile and effectiveness of the physical activity intervention for improvement of these parameters. Methods. 39 women with BMI>30 kg/m2 participated in the three-months fitness-program and followed a hypocaloric diet (1500 kCal). At the beginning and at the end of the program, the following anthropometric and biochemical parameters were measured: BMI, percentage of total and visceral fat, amount of plasma lipoproteins, cholesterol, and triglycerides. Single nucleotide polymorphisms were identified in PPARG (n=94) and PPARGC1A (n=138) genes. PPARG mRNA expression was measured through reverse transcription PCR. Results. The physical exercise intervention resulted in a significant fat mass loss in all participants (40.3±5.3% before the study vs 36.4±5.7% after the study, P<0.00001). Polymorphisms rs6442311, rs6846769, rs6846769 were associated with lower visceral fat percent, rs6442311 also correlated with PPARG expression. PPARGC1A polymorphisms rs4458444, rs2305681 were associated with plasma lipoproteins, cholesterol, and triglyceride content. Weight loss effectiveness was connected with rs17650401, rs9833097, rs12629751. Conclusions. After correction for multiple comparisons only rs17650401, of PPARGC1A gene was associated with more effective fat mass reduction. Keywords: PPARG, obesity, single nucleotide polymorphism, weight loss, exercise intervention.

OR14-05 Hepatocyte Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Offsets the Anti-Steatogenic Effects of Thiazolidinediones in Obese Male Mice

Pparg is a nuclear receptor that regulates glucose and lipid metabolism. Thiazolidinediones (TZD) are PPARG agonists that may reduce hepatic steatosis through their effects in adipose tissue. However, some studies suggest that expression and activation of hepatocyte Pparg promotes steatosis. In this study, we have assessed the relevance of hepatocyte Pparg, and its TZD-mediated activation in the development and/or reduction of steatosis, with adult-onset hepatocyte-specific Pparg knockout (PpargΔHep) mice. We reported that a single iv injection of AAV8-TBG-Cre in Pparg-floxed mice, knocked out hepatocyte Pparg expression (PpargΔHep mice), and that prevented diet-induced steatosis. In this study, a group of 5 wk-old Pparg-floxed mice were fed a low fat (LF) or a high fat (HF) diet for 7 weeks before generating control and PpargΔHep mice. Then, half of the HF-fed mice in each group were switched to a HF diet supplemented with the TZD Rosiglitazone maleate, for 5 weeks. HF diet induced mild obesity (36.8 +/- 1.4 g of body weight [BW]), while TZD slightly increased BW (41.3 +/- 1.3 g) and insulin sensitivity. Liver weight was not altered in HF-fed mice with or without TZD, and we did not observe any effect induced by PpargΔHep. Due to the mild phenotype observed in this cohort, we generated a 2nd cohort adjusting for age and length of diet. Briefly, 10 wk-old Pparg-floxed mice were fed a LF or HF diet for 16 weeks before generating control and PpargΔHep mice. Then, half of the HF-fed mice in each group were switched to a HF diet supplemented with Rosiglitazone maleate for 7 weeks. In this group of mice, HF diet induced obesity (50.1 +/- 1.05 g BW), and increased liver weight independent of hepatic Pparg expression. TZD treatment exacerbated obesity (62.4 +/- 1.2g BW) and adiposity, but increased insulin sensitivity as compared to mice fed a HF diet without TZD. Interestingly, PpargΔHep mice fed a HF diet with TZD showed enlarged subcutaneous white and brown adipose tissue weight, and a dramatic reduction in liver weight and steatosis as compared to obese control mice treated with TZD. The expression of hepatic Cd36, Cidea, Cidec, and Fabp4 was increased by TZD in a Pparg-dependent manner in HF-fed mice. Altogether, this data suggest that hepatocyte Pparg expression may offset the antisteatogenic actions of TZD in mice with severe obesity. In obese and insulin resistant individuals, TZD-mediated activation of hepatocyte Pparg may exacerbate steatosis.

Early enforcement of cell identity by a functional component of the terminally differentiated state

ABSTRACTHow progenitor cells can attain a distinct differentiated cell identity is a challenging problem given that critical transcription factors are often not unique to a differentiation process and the fluctuating signaling environment in which cells exist. Here we test the hypothesis that a unique differentiated cell identity can result from a core component of the differentiated state doubling up as a signaling protein that also drives differentiation. Using live single-cell imaging in the adipocyte differentiation system, we show that progenitor fat cells (preadipocytes) can only commit to terminally differentiate after upregulating FABP4, a lipid buffer that is highly enriched in mature adipocytes. Upon induction of adipogenesis, we show that after a long delay, cells first abruptly start to engage a positive feedback between CEBPA and PPARG before then engaging, after a second delay, a positive feedback between FABP4 and PPARG. These sequential positive feedbacks both need to engage in order to drive PPARG levels past the threshold for irreversible differentiation. In the last step before commitment, PPARG transcriptionally increases FABP4 expression while fatty-acid loaded FABP4 binds to and increases PPARG activity. Together, our study suggests a control principle for robust cell identity whereby a core component of the differentiated state also promotes differentiation from its own progenitor state.HIGHLIGHTSFatty-acid loaded FABP4 binds to and increases PPARG expression, thereby turning on PPARG positive feedback loops that further increase PPARG expression.FABP4 critically controls the second phase of adipogenesis between activation of the feedback loops and reaching the threshold to differentiate.Only a small fraction (∼10%) of the FABP4 levels typically attained in mature fat cells is needed to commit cells to the differentiated state, thus providing an explanation for why maintenance of the mature adipocyte state is so robust.