scholarly journals Inhibition of HDAC3 promotes ligand-independent PPARγ activation by protein acetylation

2014 ◽  
Vol 53 (2) ◽  
pp. 191-200 ◽  
Author(s):  
Xiaoting Jiang ◽  
Xin Ye ◽  
Wei Guo ◽  
Hongyun Lu ◽  
Zhanguo Gao
Keyword(s):  
Insulin Sensitivity ◽  
Posttranslational Modifications ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Histone Deacetylase 3 ◽  
Protein Inhibition ◽  
Diet Induced Obesity ◽  
Exogenous Ligands

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor whose activation is dependent on a ligand. PPARγ activation by exogenous ligands, such as thiazolidinediones (TZDs), is a strategy in the treatment of type 2 diabetes mellitus for the improvement of insulin sensitivity. In addition to a ligand, PPARγ function is also regulated by posttranslational modifications, such as phosphorylation, sumoylation, and ubiquitination. Herein, we report that the PPARγ protein is modified by acetylation, which induces the PPARγ function in the absence of an external ligand. We observed that histone deacetylase 3 (HDAC3) interacted with PPARγ to deacetylate the protein. In immunoprecipitation assays, the HDAC3 protein was associated with the PPARγ protein. Inhibition of HDAC3 using RNAi-mediated knockdown or HDAC3 inhibitor increased acetylation of the PPARγ protein. Furthermore, inhibition of HDAC3 enhanced the expression of PPARγ target genes such as adiponectin and aP2. The expression was associated with an increase in glucose uptake and insulin signaling in adipocytes. HDAC3 inhibition enhanced lipid accumulation during differentiation of adipocytes. PPARγ acetylation was also induced by pioglitazone and acetylation was required for PPARγ activation. In the absence of TZDs, the acetylation from HDAC3 inhibition was sufficient to induce the transcriptional activity of PPARγ. Treating diet-induced obesity mice with HDAC3 inhibitor or pioglitazone for 2 weeks significantly improved high-fat-diet-induced insulin resistance. Our results indicate that acetylation of PPARγ is a ligand-independent mechanism of PPARγ activation. HDAC3 inhibitor is a potential PPARγ activator for the improvement of insulin sensitivity.

scholarly journals The effects of obesity-associated insulin resistance on mRNA expression of peroxisome proliferator-activated receptor-γ target genes, in dogs

2007 ◽  
Vol 98 (3) ◽  
pp. 497-503 ◽  
Author(s):  
Constance Gayet ◽  
Veronique Leray ◽  
Masayuki Saito ◽  
Brigitte Siliart ◽  
Patrick Nguyen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Mrna Expression ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose And Lipid Metabolism ◽  
Visceral Adipose

Visceral adipose tissue and skeletal muscle have central roles in determining whole-body insulin sensitivity. The peroxisome proliferator-activated receptor-γ (PPARγ) is a potential mediator of insulin sensitivity. It can directly modulate the expression of genes that are involved in glucose and lipid metabolism, including GLUT4, lipoprotein lipase (LPL) and adipocytokines (leptin and adiponectin). In this study, we aimed to determine the effects of obesity-associated insulin resistance on mRNA expression of PPARγ and its target genes. Dogs were studied when they were lean and at the end of an overfeeding period when they had reached a steady obese state. The use of a sensitive, real-time PCR assay allowed a relative quantification of mRNA expression for PPARγ, LPL, GLUT4, leptin and adiponectin, in adipose tissue and skeletal muscle. In visceral adipose tissue and/or skeletal muscle, mRNA expression of PPARγ, LPL and GLUT4 were at least 2-fold less in obese and insulin-resistant dogs compared with the same animals when they were lean and insulin-sensitive. The mRNA expression and plasma concentration of leptin was increased, whereas the plasma level and mRNA expression of adiponectin was decreased, by obesity. In adipose tissue, PPARγ expression was correlated with leptin and adiponectin. These findings, in an original model of obesity induced by a prolonged period of overfeeding, showed that insulin resistance is associated with a decrease in PPARγ mRNA expression that could dysregulate expression of several genes involved in glucose and lipid metabolism.

scholarly journals Citrus ichangensisPeel Extract Exhibits Anti-Metabolic Disorder Effects by the Inhibition of PPARγand LXR Signaling in High-Fat Diet-Induced C57BL/6 Mouse

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Xiaobo Ding ◽  
Shengjie Fan ◽  
Yan Lu ◽  
Yu Zhang ◽  
Ming Gu ◽  
...  
Keyword(s):  
Fatty Acid Synthase ◽  
Target Genes ◽  
Body Weight Gain ◽  
Density Lipoprotein ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Nutritional Disorder ◽  
Peroxisome Proliferator Activated Receptor ◽  
Diet Induced Obesity

Obesity is a common nutritional disorder associated with type 2 diabetes, cardiovascular diseases, dyslipidemia, and certain cancers. In this study, we investigated the effects ofCitrus ichangensispeel extract (CIE) in high-fat (HF) diet-induced obesity mice. Female C57BL/6 mice were fed a chow diet or an HF diet alone or supplemented with 1% w/w CIE for 8 weeks. We found that CIE treatment could lower blood glucose level and improve glucose tolerance. In the HF+CIE group, body weight gain, serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) levels, and liver triglyceride (TG) and TC concentrations were significantly (P<0.05) decreased relative to those in the HF group. To elucidate the mechanism of CIE on the metabolism of glucose and lipid, related genes expression in liver were examined. In liver tissue, CIE significantly decreased the mRNA expression levels of peroxisome proliferator-activated receptorγ(PPARγ) and its target genes, such as fatty acid synthase (FAS) and acyl-CoA oxidase (ACO). Moreover, CIE also decreased the expression of liver X receptor (LXR)αandβwhich are involved in lipid and glucose metabolism. These results suggest that CIE administration could alleviate obesity and related metabolic disorders in HF diet-induced obesity mice through the inhibition of PPARγand LXR signaling.

scholarly journals Cyclin D3 Promotes Adipogenesis through Activation of Peroxisome Proliferator-Activated Receptor γ

2005 ◽  
Vol 25 (22) ◽  
pp. 9985-9995 ◽  
Author(s):  
David A. Sarruf ◽  
Irena Iankova ◽  
Anna Abella ◽  
Said Assou ◽  
Stéphanie Miard ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Nuclear Receptor ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Direct Interaction ◽  
Mitotic Division ◽  
Cyclin D3 ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Diet Induced Obesity

ABSTRACT In addition to their role in cell cycle progression, new data reveal an emerging role of D-type cyclins in transcriptional regulation and cellular differentiation processes. Using 3T3-L1 cell lines to study adipogenesis, we observed an up-regulation of cyclin D3 expression throughout the differentiation process. Surprisingly, cyclin D3 was only minimally expressed during the initial stages of adipogenesis, when mitotic division is prevalent. This seemingly paradoxical expression led us to investigate a potential cell cycle-independent role for cyclin D3 during adipogenesis. We show here a direct interaction between cyclin D3 and the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). Our experiments reveal cyclin D3 acts as a ligand-dependent PPARγ coactivator, which, together with its cyclin-dependent kinase partner, phosphorylates the A-B domain of the nuclear receptor. Overexpression and knockdown studies with cyclin D3 had marked effects on PPARγ activity and subsequently on adipogenesis. Chromatin immunoprecipitation assays confirm the participation of cyclin D3 in the regulation of PPARγ target genes. We show that cyclin D3 mutant mice are protected from diet-induced obesity, display smaller adipocytes, have reduced adipogenic gene expression, and are insulin sensitive. Our results indicate that cyclin D3 is an important factor governing adipogenesis and obesity.

scholarly journals The Nuclear Hormone Receptor PPARγas a Therapeutic Target in Major Diseases

2010 ◽  
Vol 10 ◽  
pp. 2181-2197 ◽  
Author(s):  
Martina Victoria Schmidt ◽  
Bernhard Brüne ◽  
Andreas von Knethen
Keyword(s):  
Therapeutic Target ◽  
Hormone Receptor ◽  
Target Genes ◽  
Inflammatory Responses ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Sensitizers

The peroxisome proliferator-activated receptor γ (PPARγ) belongs to the nuclear hormone receptor superfamily and regulates gene expression upon heterodimerization with the retinoid X receptor by ligating to peroxisome proliferator response elements (PPREs) in the promoter region of target genes. Originally, PPARγwas identified as being essential for glucose metabolism. Thus, synthetic PPARγagonists, the thiazolidinediones (TZDs), are used in type 2 diabetes therapy as insulin sensitizers. More recent evidence implied an important role for the nuclear hormone receptor PPARγin controlling various diseases based on its anti-inflammatory, cell cycle arresting, and proapoptotic properties. In this regard, expression of PPARγis not restricted to adipocytes, but is also found in immune cells, such as B and T lymphocytes, monocytes, macrophages, dendritic cells, and granulocytes. The expression of PPARγin lymphoid organs and its modulation of macrophage inflammatory responses, lymphocyte proliferation, cytokine production, and apoptosis underscore its immune regulating functions. Moreover, PPARγexpression is found in tumor cells, where its activation facilitates antitumorigenic actions. This review provides an overview about the role of PPARγas a possible therapeutic target approaching major, severe diseases, such as sepsis, cancer, and atherosclerosis.

scholarly journals Rhein Reduces Fat Weight indb/dbMouse and Prevents Diet-Induced Obesity in C57Bl/6 Mouse through the Inhibition of PPARγSignaling

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Yu Zhang ◽  
Shengjie Fan ◽  
Na Hu ◽  
Ming Gu ◽  
Chunxiao Chu ◽  
...  
Keyword(s):  
Target Genes ◽  
Fasting Blood Glucose ◽  
Peroxisome Proliferator ◽  
Brown Adipocytes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Levels ◽  
Rheum Palmatum ◽  
Diet Induced Obesity ◽  
Blood Glucose Levels ◽  
Underlying Mechanisms

Rheum palmatumhas been used most frequently in the weight-reducing formulae in traditional Chinese medicine. However, the components ofRheum palmatumthat play the antiobesity role are still uncertain. Here, we tested the weight-reducing effect of two majorRheum palmatumcompounds ondb/dbmouse. We found that rhein (100 mg kg−1 day−1), but not emodin, reduced the fat weight indb/dbmouse. Using diet-induced obese (DIO) C57BL/6 mice, we identified that rhein blocked high-fat diet-induced obesity, decreased fat mass and the size of white and brown adipocytes, and lowered serum cholesterol, LDL cholesterol, and fasting blood glucose levels in the mice. To elucidate the underlying mechanisms, we used reporter assay and gene expression analysis and found that rhein inhibited peroxisome proliferator-activated receptorγ(PPARγ) transactivity and the expression of its target genes, suggesting that rhein may act as a PPARγantagonist. Our data indicate that rhein may be a promising choice for antiobesity therapy.

scholarly journals Inhibition of PPARγ, adipogenesis and insulin sensitivity by MAGED1

2018 ◽  
Vol 239 (2) ◽  
pp. 167-180 ◽  
Author(s):  
Qinghua Wang ◽  
Jing Tang ◽  
Shujun Jiang ◽  
Zan Huang ◽  
Anying Song ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Neural Development ◽  
Target Genes ◽  
Late Onset ◽  
Negative Regulator ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Enhanced Secretion ◽  
Deficient Mice

Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipogenesis and a target of the thiazolidinedione (TZD) class of antidiabetic drugs; therefore, identifying novel regulators of PPARγ action in adipocytes is essential for the future development of therapeutics for diabetes. MAGE family member D1 (MAGED1), by acting as an adaptor for ubiquitin-dependent degradation pathways and a co-factor for transcription, plays an important role in neural development, cell differentiation and circadian rhythm. Here, we showed that MAGED1 expression was downregulated during adipogenesis and loss of MAGED1 promoted preadipocyte proliferation and differentiation in vitro. MAGED1 bound to PPARγ and suppressed the stability and transcriptional activity of PPARγ. Compared to WT littermates, MAGED1-deficient mice showed increased levels of PPARγ protein and its target genes, more CD29+CD34+Sca-1+ adipocyte precursors and hyperplasia of white adipose tissues (WATs). Moreover, MAGED1-deficient mice developed late-onset obesity as a result of decreased energy expenditure and physical activity. However, these mice were metabolically healthy as shown by improved glucose clearance and insulin sensitivity, normal levels of serum lipids and enhanced secretion of adipokines such as leptin and adiponectin. Taken together, our data identify MAGED1 as a novel negative regulator of PPARγ activity, adipogenesis and insulin sensitivity in mice. MAGED1 might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance.

Radioprotective effect of pioglitazone against genotoxicity induced by ionizing radiation in human healthy lymphocytes

2020 ◽  
Vol 18 ◽  
Author(s):  
Roya Kazemi ◽  
Seyed Jalal Hosseinimehr
Keyword(s):  
Ionizing Radiation ◽  
Human Lymphocytes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Mean ◽  
Anti Inflammatory ◽  
Sensitizing Effect ◽  
Binucleated Lymphocytes ◽  
Inflammatory Effect

Objective: Pioglitazone (PG) is used to control high blood sugar in patients with type 2 diabetes mellitus. PG acts as a peroxisome proliferator-activated receptor γ agonist. In addition to the insulin-sensitizing effect, PG possesses anti-inflammatory effect. In this study, the protective effect of PG was evaluated against DNA damage induced by ionizing radiation in human healthy lymphocytes. Methods: The microtubes containing human whole blood were treated with PG at various concentrations (1-50 μM) for three hours. Then, the blood samples were irradiated with X-ray. Lymphocytes were cultured for determining the frequency of micronuclei as a genotoxicity biomarker in binucleated lymphocytes. Results: The mean percentage of micronuclei was significantly increased in human lymphocytes when were exposed to IR, while it was decreased in lymphocytes pre-treated with PG. The maximum reduction in the frequency of micronuclei in irradiated lymphocytes was observed at 5 μM of PG treatment (48% decrease). Conclusion: The anti-inflammatory property is suggested the mechanism action of PG for protection human lymphocytes against genotoxicity induced by ionizing radiation.

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