scholarly journals Ectopic Overexpression of PPARγ2 in the Heart Determines Differences in Hypertrophic Cardiomyopathy After Treatment With Different Thiazolidinediones in a Mouse Model of Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Xuemei Cao ◽  
Min Mao ◽  
Junlin Diao ◽  
Yi Hou ◽  
Hong Su ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Cardiac Hypertrophy ◽  
Heart Function ◽  
Partial Agonist ◽  
Compensatory Hypertrophy ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ectopic Overexpression

The clinical controversy of rosiglitazone as a hypoglycemic agent is potentially associated with heart failure, mainly due to its potent activation of peroxisome proliferator-activated receptor γ (PPARγ). PPARγ partial agonists showed superior pharmacological profiles to rosiglitazone. This study compared differences in cardiac morphology and function of the PPARγ partial agonist CMHX008 with rosiglitazone. High-fat diet (HFD) induced obese mice, ob/ob mice and cardiomyocytes overexpressing PPARγ2 were treated with CMHX008 or rosiglitazone. Heart function, myocardial morphology, and hypertrophy-related gene expression were examined. Clinical information from patients with type 2 diabetes mellitus (T2DM) who had taken rosiglitazone and undergone Doppler echocardiography was collected. HFD and ob/ob mice significantly developed cardiac contractile dysfunction, with upregulated PPARγ2 protein levels in heart tissues. Cardiomyocytes of HFD and ob/ob mice were disorderly arranged, the cell areas expanded, and collagen accumulated. In vitro cardiomyocytes overexpressing PPARγ2 displayed obvious structural abnormalities and high mRNA levels of ANP and BNP, critical cardiac hypertrophy-related genes. HFD-fed mice treated with rosiglitazone or CMHX008 had significantly improved cardiac function, but rosiglitazone induced higher expression of ANP and βMHC and hypertrophic cardiomyopathy, while CMHX008 did not. Patients with T2DM taking rosiglitazone exhibited increased thickness of the posterior wall and the ventricular septum, suggesting cardiac hypertrophy. Our findings show that diabetic cardiomyopathy was associated with ectopic overexpression of PPARγ2. The full agonist rosiglitazone prevents cardiac dysfunction at the expense of compensatory hypertrophy, while the partial agonist CMHX008 shared a comparable protective effect without altering the structure of cardiomyocytes.

scholarly journals Chlorogenic Acid Functions as a Novel Agonist of PPARγ2 during the Differentiation of Mouse 3T3-L1 Preadipocytes

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Shu-guang Peng ◽  
Yi-lin Pang ◽  
Qi Zhu ◽  
Jing-he Kang ◽  
Ming-xin Liu ◽  
...  
Keyword(s):  
Chlorogenic Acid ◽  
Fruits And Vegetables ◽  
Quantitative Polymerase Chain Reaction ◽  
Lipid Synthesis ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Related Gene ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Impact

Rosiglitazone (RG) is a well-known activator of peroxisome proliferator-activated receptor-gamma (PPARγ) and used to treat hyperglycemia and type 2 diabetes; however, its clinical application has been confounded by adverse side effects. Here, we assessed the roles of chlorogenic acid (CGA), a phenolic secondary metabolite found in many fruits and vegetables, on the differentiation and lipolysis of mouse 3T3-L1 preadipocytes. The results showed that CGA promoted differentiation in vitro according to oil red O staining and quantitative polymerase chain reaction assays. As a potential molecular mechanism, CGA downregulated mRNA levels of the adipocyte differentiation-inhibitor gene Pref1 and upregulated those of major adipogenic transcriptional factors (Cebpb and Srebp1). Additionally, CGA upregulated the expression of the differentiation-related transcriptional factor PPARγ2 at both the mRNA and protein levels. However, following CGA intervention, the accumulation of intracellular triacylglycerides following preadipocyte differentiation was significantly lower than that in the RG group. Consistent with this, our data indicated that CGA treatment significantly upregulated the expression of lipogenic pathway-related genes Plin and Srebp1 during the differentiation stage, although the influence of CGA was weaker than that of RG. Notably, CGA upregulated the expression of the lipolysis-related gene Hsl, whereas it did not increase the expression of the lipid synthesis-related gene Dgat1. These results demonstrated that CGA might function as a potential PPARγ agonist similar to RG; however, the impact of CGA on lipolysis in 3T3-L1 preadipocytes differed from that of RG.

Molecular mechanism of 1,25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells

2006 ◽  
Vol 290 (5) ◽  
pp. E916-E924 ◽  
Author(s):  
Juan Kong ◽  
Yan Chun Li
Keyword(s):  
Cell Differentiation ◽  
Molecular Mechanism ◽  
Regulatory Element ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Dihydroxyvitamin D3 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels

We have investigated the molecular mechanism whereby 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits adipogenesis in vitro. 1,25(OH)2D3 blocks 3T3-L1 cell differentiation into adipocytes in a dose-dependent manner; however, the inhibition is ineffective 24–48 h after the differentiation is initiated, suggesting that 1,25(OH)2D3 inhibits only the early events of the adipogenic program. Treatment of 3T3-L1 cells with 1,25(OH)2D3 does not block the mitotic clonal expansion or C/EBPβ induction; rather, 1,25(OH)2D3 blocks the expression of C/EBPα, peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein-1, and other downstream adipocyte markers. The inhibition by 1,25(OH)2D3 is reversible, since removal of 1,25(OH)2D3 from the medium restores the adipogenic process with only a temporal delay. Interestingly, although the vitamin D receptor (VDR) protein is barely detectable in 3T3-L1 preadipocytes, its levels are dramatically increased during the early phase of adipogenesis, peaking at 4–8 h and subsiding afterward throughout the rest of the differentiation program; 1,25(OH)2D3 treatment appears to stabilize the VDR protein levels. Consistently, adenovirus-mediated overexpression of human (h) VDR in 3T3-L1 cells completely blocks the adipogenic program, confirming that VDR is inhibitory. Inhibition of adipocyte differentiation by 1,25(OH)2D3 is ameliorated by troglitazone, a specific PPARγ antagonist; conversely, hVDR partially suppresses the transacting activity of PPARγ but not of C/EBPβ or C/EBPα. Moreover, 1,25(OH)2D3 markedly suppresses C/EBPα and PPARγ mRNA levels in mouse epididymal fat tissue culture. Taken together, these data indicate that the blockade of 3T3-L1 cell differentiation by 1,25(OH)2D3 occurs at the postclonal expansion stages and involves direct suppression of C/EBPα and PPARγ upregulation, antagonization of PPARγ activity, and stabilization of the inhibitory VDR protein.

Proadipogenic effect of leptin on rat preadipocytes in vitro: activation of MAPK and STAT3 signaling pathways

2002 ◽  
Vol 282 (4) ◽  
pp. C853-C863 ◽  
Author(s):  
F. Machinal-Quélin ◽  
M. N. Dieudonné ◽  
M. C. Leneveu ◽  
R. Pecquery ◽  
Y. Giudicelli
Keyword(s):  
Subcutaneous Fat ◽  
Cell Types ◽  
Binding Activity ◽  
Mitogen Activated Protein Kinase ◽  
Cell Counting ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Stat3 Phosphorylation

Because leptin has recently been shown to induce proliferation and/or differentiation of different cell types through different pathways, the aim of the present study was to investigate, in vitro, the influence of leptin on adipogenesis in rat preadipocytes. A prerequisite to this study was to identify leptin receptors (Ob-Ra and Ob-Rb) in preadipocytes from femoral subcutaneous fat. We observed that expressions of Ob-Ra and Ob-Rb increase during adipogenesis. Furthermore, leptin induces an increase of p42/p44 mitogen-activated protein kinase phosphorylated isoforms in both confluent and differentiated preadipocytes and of STAT3 phosphorylation only in confluent preadipocytes. Moreover, exposure to leptin promoted activator protein-1 complex DNA binding activity in confluent preadipocytes. Finally, exposure of primary cultured preadipocytes from the subcutaneous area to leptin (10 nM) resulted in an increased proliferation ([3H]thymidine incorporation and cell counting) and differentiation (glycerol-3-phosphate dehydrogenase activity and mRNA levels of lipoprotein lipase, peroxisome proliferator-activated receptor-γ2, and c-fos). Altogether, these results indicate that, in vitro at least, leptin through its functional receptors exerts a proadipogenic action in subcutaneous preadipocytes.

scholarly journals N-Acetylcysteine Inhibits Lipids Production in Mature Adipocytes through the Inhibition of Peroxisome Proliferator-Activated Receptor 

2020 ◽  
pp. 17-29
Author(s):  
Daniela Soto ◽  
Claudia Martini ◽  
Evelyn Frontera ◽  
Laura Montaldo ◽  
Maria C. Vila ◽  
...  
Keyword(s):  
In Vitro Study ◽  
Nutritional Supplement ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mrna And Protein Expression ◽  
Species Production ◽  
Lipids Production

Aims: Reports regarding the effects of antioxidants in obesity have been contradictory. Antioxidant N-acetylcysteine is usually considered a nutritional supplement. Our aim is to evaluate bioactivity of N-acetylcysteine (NAC) on mature adipocytes, which is a close model to in vivo condition. Study Design: In vitro study. Place and Duration of Study: Department of Basic Science (Universidad Nacional de Lujan), Department of Chemical Biology (Universidad de Buenos Aires), CONICET – INEDES and CONICET – IQUIBICEN, between March 2017 and June 2019. Methodology: We evaluated the bioactivity of different concentrations of NAC for 5 days (0.01 mM to 5 mM) on fully differentiated 3T3-L1 cells (mature adipocytes). Results: We demonstrated that NAC treatment was not toxic to mature adipocytes. Only 5mM NAC inhibited reactive oxygen species production. 5 mM NAC treatment resulted in a 60% decrease in cellular triglycerides content and inhibited 70% cholesterol accumulation.  We also determined the mRNA and protein expression levels of Peroxisome Proliferator-Activated Receptor g as well as, mRNA levels of lipid protein Perilipin in NAC treated adipocytes; we observed that 5mM NAC treatment caused nearly 30% decrease in the expression of these parameters. Conclusion: These results suggest that NAC could avoid lipid accumulation in mature adipocytes; the antioxidant NAC could be beneficial in obesity treatment.

scholarly journals MBX-102/JNJ39659100, a Novel Peroxisome Proliferator-Activated Receptor-Ligand with Weak Transactivation Activity Retains Antidiabetic Properties in the Absence of Weight Gain and Edema

2009 ◽  
Vol 23 (7) ◽  
pp. 975-988 ◽  
Author(s):  
Francine M. Gregoire ◽  
Fang Zhang ◽  
Holly J. Clarke ◽  
Thomas A. Gustafson ◽  
Dorothy D. Sears ◽  
...  
Keyword(s):  
Target Genes ◽  
Partial Agonist ◽  
Oral Glucose ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Sensitizer ◽  
Glucose Lowering ◽  
Ppar Γ ◽  
Primary Mouse

Abstract MBX-102/JNJ39659100 (MBX-102) is in clinical development as an oral glucose-lowering agent for the treatment of type 2 diabetes. MBX-102 is a nonthiazolidinedione (TZD) selective partial agonist of peroxisome proliferator-activated receptor (PPAR)-γ that is differentiated from the TZDs structurally, mechanistically, preclinically and clinically. In diabetic rodent models, MBX-102 has insulin-sensitizing and glucose-lowering properties comparable to TZDs without dose-dependent increases in body weight. In vitro, in contrast with full PPAR-γ agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR-γ target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR-γ agonists, MBX-102 displays differential interactions with the PPAR-γ ligand binding domain and possesses reduced ability to recruit coactivators. Interestingly, in primary mouse macrophages, MBX-102 displays enhanced antiinflammatory properties compared with other PPAR-γ or α/γ agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR-γ modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR-γ side effects and may represent the next generation insulin sensitizer.

The Pro-Differentiation Effect of Doxycycline on Human SZ95 Sebocytes

Dermatology ◽  
2020 ◽  
pp. 1-5
Author(s):  
Christos C. Zouboulis ◽  
Síona Ní Raghallaigh ◽  
Gerd Schmitz ◽  
Frank C. Powell
Keyword(s):  
Lipid Content ◽  
Acne Vulgaris ◽  
Cell Number ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Sebaceous Glands ◽  
Peroxisome Proliferator Activated Receptor ◽  
New Findings

Background: Despite their widespread clinical use in both acne vulgaris and rosacea, the effects of tetracyclines on sebocytes have not been investigated until now. Sebaceous glands are central to the pathogenesis of acne and may be important in the development of rosacea. Objective: The aim of this study was to assess the effects of doxycycline on the immortalized SZ95 sebaceous gland cell line as a model for understanding possible effectiveness on the sebaceous glands in vivo. Methods: The effects of doxycycline on SZ95 sebocyte numbers, viability, and lipid content as well as its effects on the mRNA levels of peroxisome proliferator-activated receptors α and γ, in comparison to the peroxisome proliferator-activated receptor γ agonist troglitazone, were investigated. Results: Doxycycline reduced the cell number and increased the lipid content of SZ95 sebocytes in vitro after 2 days of treatment. These doxycycline effects may be explained by an upregulation of peroxisome proliferator-activated receptor γ mRNA levels at 12 and 24 h, whereas troglitazone already upregulated peroxisome proliferator-activated receptor γ levels after 6 h. Both compounds did not influence peroxisome proliferator-activated receptor α mRNA levels. Conclusion: These new findings illustrate a previously unknown effect of doxycycline on sebocytes, which may be relevant to their modulation of disorders of the pilosebaceous unit, such as acne vulgaris and rosacea.

scholarly journals Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPARα in murine heart

2005 ◽  
Vol 385 (2) ◽  
pp. 469-477 ◽  
Author(s):  
Biao LU ◽  
Yan J. JIANG ◽  
Yaling ZHOU ◽  
Fred Y. XU ◽  
Grant M. HATCH ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Tissue Expression ◽  
In Vitro Transcription ◽  
Amino Acid Sequences ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor

AGPAT (1-acyl-sn-glycerol 3-phosphate acyltransferase) exists in at least five isoforms in humans, termed as AGPAT1, AGPAT2, AGPAT3, AGPAT4 and AGPAT5. Although they catalyse the same biochemical reaction, their relative function, tissue expression and regulation are poorly understood. Linkage studies in humans have revealed that AGPAT2 contributes to glycerolipid synthesis and plays an important role in regulating lipid metabolism. We report the molecular cloning, tissue distribution, and enzyme characterization of mAGPATs (murine AGPATs) and regulation of cardiac mAGPATs by PPARα (peroxisome-proliferator-activated receptor α). mAGPATs demonstrated differential tissue expression profiles: mAGPAT1 and mAGPAT3 were ubiquitously expressed in most tissues, whereas mAGPAT2, mAGPAT4 and mAGPAT5 were expressed in a tissue-specific manner. mAGPAT2 expressed in in vitro transcription and translation reactions and in transfected COS-1 cells exhibited specificity for 1-acyl-sn-glycerol 3-phosphate. When amino acid sequences of five mAGPATs were compared, three highly conserved motifs were identified, including one novel motif/pattern KX2LX6GX12R. Cardiac mAGPAT activities were 25% lower (P<0.05) in PPARα null mice compared with wild-type. In addition, cardiac mAGPAT activities were 50% lower (P<0.05) in PPARα null mice fed clofibrate compared with clofibrate fed wild-type animals. This modulation of AGPAT activity was accompanied by significant enhancement/reduction of the mRNA levels of mAGPAT3/mAGPAT2 respectively. Finally, mRNA expression of cardiac mAGPAT3 appeared to be regulated by PPARα activation. We conclude that cardiac mAGPAT activity may be regulated by both the composition of mAGPAT isoforms and the levels of each isoform.

Peroxisome proliferator-activated receptor-γ activators inhibit endothelin-1-related cardiac hypertrophy in rats

2002 ◽  
Vol 103 (s2002) ◽  
pp. 16S-20S ◽  
Author(s):  
Satoshi SAKAI ◽  
Takashi MIYAUCHI ◽  
Yoko IRUKAYAMA-TOMOBE ◽  
Takehiro OGATA ◽  
Katsutoshi GOTO ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Left Ventricular ◽  
Sham Operation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Endothelin 1 ◽  
Vehicle Treatment ◽  
Pioglitazone Treatment

Endothelin-1 (ET-1) causes cardiac hypertrophy, and ET receptor antagonists inhibit the development of cardiac hypertrophy in vitro and in vivo. Peroxisome proliferator-activated receptor γ (PPARγ), a member of the family of nuclear receptors, suppresses activator protein-1 (AP-1). We investigated the effects of the thiazolidinediones troglitazone and pioglitazone, activators of PPARγ, on cardiac hypertrophy due to pressure overload provoked by abdominal aortic banding (AB) in rats. Rats were divided into four groups: sham operation with vehicle treatment (n = 5); AB surgery with vehicle treatment (n = 6); AB surgery with troglitazone treatment (100mg·kg-1·day-1; n = 5); and AB surgery with pioglitazone treatment (10mg·kg-1·day-1; n = 8). Treatments were started 7 days before AB surgery, and left ventricular (LV) hypertrophy was assessed 24h after surgery. The ratio of LV weight/body weight (BW) was significantly increased in AB rats compared with sham-operated rats; treatment of AB rats with troglitazone or pioglitazone significantly inhibited the increase in LV weight/BW. Expression of ET-1 mRNA was markedly enhanced in the left ventricles of AB rats; treatment with troglitazone or pioglitazone lowered expression significantly. Suppression of cardiac hypertrophy by pioglitazone treatment was accompanied by a decrease in expression of the gene encoding brain natriuretic factor, a molecular marker for cardiac hypertrophy, in AB rats. Because the ET-1 gene has AP-1 response elements in its 5´-flanking region, the thiazolidinediones troglitazone and pioglitazone may inhibit cardiac hypertrophy partly through suppression of AP-1-induced ET-1 gene up-regulation.

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