scholarly journals The Role of ATF-2 Family Transcription Factors in Adipocyte Differentiation: Antiobesity Effects of p38 Inhibitors

2009 ◽  
Vol 30 (3) ◽  
pp. 613-625 ◽  
Author(s):  
Toshio Maekawa ◽  
Wanzhu Jin ◽  
Shunsuke Ishii
Keyword(s):  
Transcription Factors ◽  
Adipocyte Differentiation ◽  
Physiological Role ◽  
Bone Morphogenetic Protein 2 ◽  
Peroxisome Proliferator ◽  
Necrosis Factor Alpha ◽  
Peroxisome Proliferator Activated Receptor ◽  
P38 Inhibitor ◽  
Morphogenetic Protein

ABSTRACT ATF-2 is a member of the ATF/CREB family of transcription factors and is activated by stress-activated protein kinases, such as p38. To analyze the physiological role of ATF-2 family transcription factors, we have generated mice with mutations in Atf-2 and Cre-bpa, an Atf-2-related gene. The trans-heterozygotes of both mutants were lean and had reduced white adipose tissue (WAT). ATF-2 and CRE-BPa were required for bone morphogenetic protein 2 (BMP-2)-and p38-dependent induction of peroxisome proliferator-activated receptor γ2 (PPARγ2), a key transcription factor mediating adipocyte differentiation. Since stored fat supplies have been recognized as a possible target for antiobesity treatments, we tested whether inhibition of the p38-ATF-2 pathway suppresses adipocyte differentiation and leads to reduced WAT by treating mice with a p38 inhibitor for long periods of time. High-fat diet (HFD)-induced obesity was significantly reduced in mice fed the p38 inhibitor. Furthermore, the p38 inhibitor alleviated HFD-induced insulin resistance. In p38 inhibitor-treated mice, macrophage infiltration into WAT was reduced and the tumor necrosis factor alpha (TNF-α) levels were lower than control mice. Thus, p38 inhibitors may provide a novel antiobesity treatment.

scholarly journals Evidence for the Regulatory Role of Lipocalin 2 in High-Fat Diet-Induced Adipose Tissue Remodeling in Male Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (10) ◽  
pp. 3525-3538 ◽  
Author(s):  
Hong Guo ◽  
Merlijn Bazuine ◽  
Daozhong Jin ◽  
Merry M. Huang ◽  
Samuel W. Cushman ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Adipocyte Differentiation ◽  
Tissue Remodeling ◽  
Peroxisome Proliferator ◽  
Lipocalin 2 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Adipose Tissue Remodeling ◽  
Fat Depot

Lipocalin 2 (Lcn2) has previously been characterized as an adipokine/cytokine playing a role in glucose and lipid homeostasis. In this study, we investigate the role of Lcn2 in adipose tissue remodeling during high-fat diet (HFD)-induced obesity. We find that Lcn2 protein is highly abundant selectively in inguinal adipose tissue. During 16 weeks of HFD feeding, the inguinal fat depot expanded continuously, whereas the expansion of the epididymal fat depot was reduced in both wild-type (WT) and Lcn2−/− mice. Interestingly, the depot-specific effect of HFD on fat mass was exacerbated and appeared more pronounced and faster in Lcn2−/− mice than in WT mice. In Lcn2−/− mice, adipocyte hypertrophy in both inguinal and epididymal adipose tissue was more profoundly induced by age and HFD when compared with WT mice. The expression of peroxisome proliferator-activated receptor-γ protein was significantly down-regulated, whereas the gene expression of extracellular matrix proteins was up-regulated selectively in epididymal adipocytes of Lcn2−/− mice. Consistent with these observations, collagen deposition was selectively higher in the epididymal, but not in the inguinal adipose depot of Lcn2−/− mice. Administration of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone (Rosi) restored adipogenic gene expression. However, Lcn2 deficiency did not alter the responsiveness of adipose tissue to Rosi effects on the extracellular matrix expression. Rosi treatment led to the further enlargement of adipocytes with improved metabolic activity in Lcn2−/− mice, which may be associated with a more pronounced effect of Rosi treatment in reducing TGF-β in Lcn2−/− adipose tissue. Consistent with these in vivo observations, Lcn2 deficiency reduces the adipocyte differentiation capacity of stromal-vascular cells isolated from HFD-fed mice in these cells. Herein Rosi treatment was again able to stimulate adipocyte differentiation to a similar extent in WT and Lcn2−/− inguinal and epididymal stromal-vascular cells. Thus, combined, our data indicate that Lcn2 has a depot-specific role in HFD-induced adipose tissue remodeling.

scholarly journals Cyclin G2 Regulates Adipogenesis through PPARγ Coactivation

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5247-5254 ◽  
Author(s):  
Victor Aguilar ◽  
Jean-Sébastien Annicotte ◽  
Xavier Escote ◽  
Joan Vendrell ◽  
Dominique Langin ◽  
...  
Keyword(s):  
Adipocyte Differentiation ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Cell Cycle Regulators ◽  
Luciferase Reporter Gene ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cyclin G2 ◽  
Regulatory Effects

Cell cycle regulators such as cyclins, cyclin-dependent kinases, or retinoblastoma protein play important roles in the differentiation of adipocytes. In the present paper, we investigated the role of cyclin G2 as a positive regulator of adipogenesis. Cyclin G2 is an unconventional cyclin which expression is up-regulated during growth inhibition or apoptosis. Using the 3T3-F442A cell line, we observed an up-regulation of cyclin G2 expression at protein and mRNA levels throughout the process of cell differentiation, with a further induction of adipogenesis when the protein is transiently overexpressed. We show here that the positive regulatory effects of cyclin G2 in adipocyte differentiation are mediated by direct binding of cyclin G2 to peroxisome proliferator-activated receptor γ (PPARγ), the key regulator of adipocyte differentiation. The role of cyclin G2 as a novel PPARγ coactivator was further demonstrated by chromatin immunoprecipitation assays, which showed that the protein is present in the PPARγ-responsive element of the promoter of aP2, which is a PPARγ target gene. Luciferase reporter gene assays, showed that cyclin G2 positively regulates the transcriptional activity of PPARγ. The role of cyclin G2 in adipogenesis is further underscored by its increased expression in mice fed a high-fat diet. Taken together, our results demonstrate a novel role for cyclin G2 in the regulation of adipogenesis.

Effect of vitamin D on isoprenaline-induced myocardial infarction in rats: possible role of peroxisome proliferator-activated receptor-γ

2017 ◽  
Vol 95 (6) ◽  
pp. 641-646 ◽  
Author(s):  
Ola Ahmed El-Gohary ◽  
Mona Maher Allam
Keyword(s):  
Myocardial Infarction ◽  
Vitamin D ◽  
Diglycidyl Ether ◽  
Peroxisome Proliferator ◽  
Oxidative Stress Biomarkers ◽  
Cardiac Damage ◽  
Necrosis Factor Alpha ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Infarct-like lesion induced by isoprenaline is a well-known model to study myocardial infarction (MI). Vitamin D has been shown to have anti-inflammatory and antioxidant effects. Recent studies highlighted cross talk between vitamin D and peroxisome proliferator-activated receptor gamma (PPAR-γ). The present study was designed to investigate the effect of pretreatment with vitamin D on the isoprenaline-induced infarct-like lesion in rats and the role of PPAR-γ as a novel mechanism in vitamin-D-mediated cardioprotective effect. Markers chosen to assess cardiac damage included serum level of creatine kinase (CK), lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Cardiac contents of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH) were also assessed. Furthermore, ECG monitoring and measurement of injury extension were carried out. Isoprenaline increased the level of cardiac enzymes, as well as inflammatory and oxidative stress biomarkers. In addition, it produced ST-segment elevation. Pretreatment with vitamin D significantly improved previous parameters. The prior treatment with bisphenol A diglycidyl ether (BADGE), a PPAR-γ antagonist, significantly attenuated the protective effect of vitamin D. In conclusion, vitamin D can be demonstrated as a promising cardioprotective agent in MI and PPAR-γ significantly contributes toward vitamin-D-mediated protection.

scholarly journals Association Between BMP2 Functional Polymorphisms and Sheep Tail Type

Animals ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 739
Author(s):  
Zengkui Lu ◽  
Jianbin Liu ◽  
Jilong Han ◽  
Bohui Yang
Keyword(s):  
Tail Length ◽  
Cellular Level ◽  
Fat Deposition ◽  
Bone Morphogenetic Protein 2 ◽  
Peroxisome Proliferator ◽  
Nucleotide Polymorphisms ◽  
Peroxisome Proliferator Activated Receptor ◽  
Functional Polymorphisms ◽  
Genotype Frequencies ◽  
Morphogenetic Protein

Bone morphogenetic protein 2 (BMP2) is strongly selected in both fat-tailed and thin-tailed sheep and may be a candidate gene for sheep tail type selection. However, the mechanism of action of BMP2 in sheep tail fat deposition remains unclear. This study investigated genetic variation and haplotype combinations of the BMP2 gene in sheep with different tail types, aiming to reveal the molecular mechanism of BMP2 in sheep tail fat deposition. We detected a total of three single nucleotide polymorphisms (SNPs) (g.48401619 T > A, g.48401272 C > A, and g.48401136 C > T) among 533 sheep. The alleles and genotype frequencies of these SNPs were in Hardy–Weinberg equilibrium and showed significant correlations with tail length. Linkage disequilibrium existed between the g.48401272 C > A and g.48401136 C > T sites, where CACT was the predominant genotype. At the cellular level, the expression levels of peroxisome proliferator-activated receptor gamma (PPARγ) and lipoprotein lipase (LPL) were upregulated after BMP2 overexpression; there were significantly higher levels of PPARγ than controls at 0 d and 1 d, and of LPL than controls at 1 d and 7 d. These results indicate that the BMP2 gene may participate in sheep tail fat deposition and could be used for molecular-marker-assisted selection of sheep tail type.

BRCC36 promotes intestinal mucosal barrier injury caused by BMP2 after ischemia-reperfusion via inhibiting PPARγ signaling

2021 ◽  
Author(s):  
Jin-Ming Zhang ◽  
Kun-Nan Wang ◽  
Yun Zhang ◽  
Jun-Ze Zhang ◽  
Xin-Pu Yuan ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Bone Morphogenetic Protein 2 ◽  
Mucosal Barrier ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Intestinal Mucosal Barrier ◽  
Morphogenetic Protein ◽  
Mucosal Barrier Injury ◽  
Brca1 Brca2 ◽  
Intestinal Ischemia Reperfusion

Abstract As one of the most common pathological changes in trauma and surgery practice, intestinal ischemia-reperfusion (I/R) injury is regarded as a major precipitating factor in the occurrence and development of fatal diseases. BRCA1-BRCA2-containing complex subunit 36 (BRCC36), a deubiquitinase, has been proved important in a variety of pathophysiological processes such as DNA repair, cell cycle regulation, tumorigenesis and inflammatory response. However, the effect of BRCC36 on intestinal mucosal barrier injury after I/R has not been fully elucidated. Our research found that BRCC36 aggravated intestinal mucosal barrier injury caused by BMP2 (Bone morphogenetic protein 2) after I/R by downregulating PPARγ (Peroxisome proliferator-activated receptor-γ) signaling. These results suggested that BRCC36/PPARγ axis might serve as a potential therapeutic target for preventing intestinal mucosal barrier injury after I/R.

Role of intracellular calcium in human adipocyte differentiation

2000 ◽  
Vol 3 (2) ◽  
pp. 75-82 ◽  
Author(s):  
HANG SHI ◽  
YUAN-DI HALVORSEN ◽  
PAMELA N. ELLIS ◽  
WILLIAM O. WILKISON ◽  
MICHAEL B. ZEMEL
Keyword(s):  
Intracellular Calcium ◽  
Adipocyte Differentiation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Human Adipocyte ◽  
Gpdh Activity ◽  
Early Stages ◽  
Triglyceride Accumulation ◽  
Mild Stimulation

Shi, Hang, Yuan-Di Halvorsen, Pamela N. Ellis, William O. Wilkison, and Michael B. Zemel. Role of intracellular calcium in human adipocyte differentiation. Physiol Genomics 3: 75–82, 2000.—Intracellular calcium ([Ca2+]i) modulates adipocyte lipid metabolism and inhibits the early stages of murine adipogenesis. Consequently, we evaluated effects of increasing [Ca2+]i in early and late stages of human adipocyte differentiation. Increasing [Ca2+]i with either thapsigargin or A23187 at 0–1 h of differentiation markedly suppressed differentiation, with a 40–70% decrease in triglyceride accumulation and glycerol-3 phosphate dehydrogenase (GPDH) activity ( P < 0.005). However, a 1-h pulse of either agent at 47–48 h only modestly inhibited differentiation. Sustained, mild stimulation of Ca2+ influx with either agouti protein or 10 mM KCl-induced depolarization during 0–48 h of differentiation inhibited triglyceride accumulation and GPDH activity by 20–70% ( P < 0.05) and markedly suppressed peroxisome proliferator-activated receptor gamma (PPARγ) expression. These effects were reversed by Ca2+ channel antagonism. In contrast, Ca2+ pulses late in differentiation (71–72 h or 48–72 h) markedly increased these markers of differentiation. Thus increasing [Ca2+]i appears to exert a biphasic regulatory role in human adipocyte differentiation, inhibiting the early stages while promoting the late stage of differentiation and lipid filling.

scholarly journals Retinoic acid blocks adipogenesis by inhibiting C/EBPbeta-mediated transcription.

1997 ◽  
Vol 17 (3) ◽  
pp. 1552-1561 ◽  
Author(s):  
E J Schwarz ◽  
M J Reginato ◽  
D Shao ◽  
S L Krakow ◽  
M A Lazar
Keyword(s):  
Transcription Factors ◽  
Retinoic Acid ◽  
Transcriptional Activation ◽  
Adipocyte Differentiation ◽  
Ectopic Expression ◽  
Transient Transfection ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Necessary And Sufficient ◽  
Sequential Induction

Adipocyte differentiation is thought to involve sequential induction of the transcription factors C/EBPbeta, peroxisome proliferator-activated receptor gamma (PPARgamma), and C/EBPalpha. C/EBPalpha expression is both necessary and sufficient for adipocyte differentiation. Here we report that ectopic expression of either C/EBPalpha or C/EBPbeta induces PPARgamma expression and adipogenesis and that retinoic acid (RA) completely inhibits adipogenesis by either form of C/EBP. In studies of normal preadipocytes, RA does not prevent C/EBPbeta induction but blocks induction of PPARgamma, C/EBPalpha, and adipogenesis. In transient transfection studies, liganded RA receptor (RAR) specifically blocks transcriptional activation by either C/EBPalpha or C/EBPbeta. These results strongly suggest that C/EBPalpha substitutes for C/EBPbeta to induce adipocyte differentiation and that liganded RAR inhibits adipogenesis by blocking C/EBPbeta-mediated induction of downstream genes.

scholarly journals Mechanical Strain Inhibits Adipogenesis in Mesenchymal Stem Cells by Stimulating a Durable β-Catenin Signal

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 6065-6075 ◽  
Author(s):  
Buer Sen ◽  
Zhihui Xie ◽  
Natasha Case ◽  
Meiyun Ma ◽  
Clinton Rubin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Glycogen Synthase ◽  
Mechanical Strain ◽  
Bone Morphogenetic Protein 2 ◽  
Peroxisome Proliferator ◽  
Glycogen Synthase Kinase 3Β ◽  
Peroxisome Proliferator Activated Receptor ◽  
Morphogenetic Protein ◽  
Adiponectin Mrna

The ability of exercise to decrease fat mass and increase bone mass may occur through mechanical biasing of mesenchymal stem cells (MSCs) away from adipogenesis and toward osteoblastogenesis. C3H10T1/2 MSCs cultured in highly adipogenic medium express peroxisome proliferator-activated receptor γ and adiponectin mRNA and protein, and accumulate intracellular lipid. Mechanical strain applied for 6 h daily inhibited expression of peroxisome proliferator-activated receptor γ and adiponectin mRNA by up to 35 and 50%, respectively, after 5 d. A decrease in active and total β-catenin levels during adipogenic differentiation was entirely prevented by daily application of mechanical strain; furthermore, strain induced β-catenin nuclear translocation. Inhibition of glycogen synthase kinase-3β by lithium chloride or SB415286 also prevented adipogenesis, suggesting that preservation of β-catenin levels was important to strain inhibition of adipogenesis. Indeed, mechanical strain inactivated glycogen synthase kinase-3β, which was preceded by Akt activation, indicating that strain transmits antiadipogenic signals through this pathway. Cells grown under adipogenic conditions showed no increase in osteogenic markers runt-related transcription factor (Runx) 2 and osterix (Osx); subsequent addition of bone morphogenetic protein 2 for 2 d increased Runx2 but not Osx expression in unstrained cultures. When cultures were strained for 5 d before bone morphogenetic protein 2 addition, Runx2 mRNA increased more than in unstrained cultures, and Osx expression more than doubled. As such, mechanical strain enhanced MSC potential to enter the osteoblast lineage despite exposure to adipogenic conditions. Our results indicate that MSC commitment to adipogenesis can be suppressed by mechanical signals, allowing other signals to promote osteoblastogenesis. These data suggest that positive effects of exercise on both fat and bone may occur during mesenchymal lineage selection.

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