scholarly journals Defective thermoregulation, impaired lipid metabolism, but preserved adrenergic induction of gene expression in brown fat of mice lacking C/EBPβ

2005 ◽  
Vol 389 (1) ◽  
pp. 47-56 ◽  
Author(s):  
M. Carmen CARMONA ◽  
Elayne HONDARES ◽  
M. Luisa RODRÍGUEZ DE LA CONCEPCIÓN ◽  
Víctor RODRÍGUEZ-SUREDA ◽  
Julia PEINADO-ONSURBE ◽  
...  
Keyword(s):  
Gene Expression ◽  
Uncoupling Protein ◽  
Marker Gene ◽  
Gene Promoter ◽  
Brown Fat ◽  
Specific Marker ◽  
Peroxisome Proliferator ◽  
Inhibitory Protein ◽  
Brown Adipocytes ◽  
Peroxisome Proliferator Activated Receptor

C/EBPβ (CCAAT/enhancer-binding protein β) is a transcriptional regulator of the UCP1 (uncoupling protein-1) gene, the specific marker gene of brown adipocytes that is responsible for their thermogenic capacity. To investigate the role of C/EBPβ in brown fat, we studied the C/EBPβ-null mice. When placed in the cold, C/EBPβ−/− mice did not maintain body temperature. This cold-sensitive phenotype occurred, although UCP1 and PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α) gene expression was unaltered in brown fat of C/EBPβ−/− mice. The UCP1 gene promoter was repressed by the truncated inhibitory C/EBPβ isoform LIP (liver-enriched transcriptional inhibitory protein, the truncated inhibitory C/EBPβ isoform). Since C/EBPβ-null mice lack both C/EBPβ isoforms, active LAP (liver-enriched transcriptional activatory protein, the active C/EBPβ isoform) and LIP, the absence of LIP may have a stronger effect than the absence of LAP upon UCP1 gene expression. Gene expression for UCP2 and UCP3 was not impaired in all tissues analysed. In primary brown adipocytes from C/EBPβ−/− mice, induction of gene expression by noradrenaline was preserved. In contrast, the expression of genes related to lipid storage was impaired, as was the amount of triacylglycerol mobilized after acute cold exposure in brown fat from C/EBPβ−/− mice. LPL (lipoprotein lipase) activity was also impaired in brown fat, but not in other tissues of C/EBPβ−/− mice. LPL protein levels were also diminished, but this effect was independent of changes in LPL mRNA, suggesting that C/EBPβ is involved in the post-transcriptional regulation of LPL gene expression in brown fat. In summary, defective thermoregulation owing to the lack of C/EBPβ is associated with the reduced capacity to supply fatty acids as fuels to sustain brown fat thermogenesis.

scholarly journals Dopamine directly increases mitochondrial mass and thermogenesis in brown adipocytes

2017 ◽  
Vol 58 (2) ◽  
pp. 57-66 ◽  
Author(s):  
Rose Kohlie ◽  
Nina Perwitz ◽  
Julia Resch ◽  
Sebastian M Schmid ◽  
Hendrik Lehnert ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Energy Homeostasis ◽  
Uncoupling Protein ◽  
Brown Adipocyte ◽  
Peroxisome Proliferator ◽  
Cellular Mechanisms ◽  
Brown Adipocytes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mitochondrial Mass ◽  
Brown Adipose

Brown adipose tissue (BAT) is key to energy homeostasis. By virtue of its thermogenic potential, it may dissipate excessive energy, regulate body weight and increase insulin sensitivity. Catecholamines are critically involved in the regulation of BAT thermogenesis, yet research has focussed on the effects of noradrenaline and adrenaline. Some evidence suggests a role of dopamine (DA) in BAT thermogenesis, but the cellular mechanisms involved have not been addressed. We employed our extensively characterised murine brown adipocyte cells. D1-like and D2-like receptors were detectable at the protein level. Stimulation with DA caused an increase in cAMP concentrations. Oxygen consumption rates (OCR), mitochondrial membrane potential (Δψm) and uncoupling protein 1 (UCP1) levels increased after 24 h of treatment with either DA or a D1-like specific receptor agonist. A D1-like receptor antagonist abolished the DA-mediated effect on OCR, Δψm and UCP1. DA induced the release of fatty acids, which did not additionally alter DA-mediated increases of OCR. Mitochondrial mass (as determined by (i) CCCP- and oligomycin-mediated effects on OCR and (ii) immunoblot analysis of mitochondrial proteins) also increased within 24 h. This was accompanied by an increase in peroxisome proliferator-activated receptor gamma co-activator 1 alpha protein levels. Also, DA caused an increase in p38 MAPK phosphorylation and pharmacological inhibition of p38 MAPK abolished the DA-mediated effect on Δψm. In summary, our study is the first to reveal direct D1-like receptor and p38 MAPK-mediated increases of thermogenesis and mitochondrial mass in brown adipocytes. These results expand our understanding of catecholaminergic effects on BAT thermogenesis.

scholarly journals A meta-analysis study of gene expression datasets in mouse liver under PPARα knockout

2013 ◽  
Vol 95 (2-3) ◽  
pp. 78-88 ◽  
Author(s):  
KAN HE ◽  
ZHEN WANG ◽  
QISHAN WANG ◽  
YUCHUN PAN
Keyword(s):  
Gene Expression ◽  
Mouse Liver ◽  
Meta Analysis ◽  
Expression Patterns ◽  
Hepatic Tissue ◽  
Marker Genes ◽  
Specific Marker ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Microarray Datasets

SummaryGene expression profiling of peroxisome-proliferator-activated receptor α (PPARα) has been used in several studies, but there were no consistent results on gene expression patterns involved in PPARα activation in genome-wide due to different sample sizes or platforms. Here, we employed two published microarray datasets both PPARα dependent in mouse liver and applied meta-analysis on them to increase the power of the identification of differentially expressed genes and significantly enriched pathways. As a result, we have improved the concordance in identifying many biological mechanisms involved in PPARα activation. We suggest that our analysis not only leads to more identified genes by combining datasets from different resources together, but also provides some novel hepatic tissue-specific marker genes related to PPARα according to our re-analysis.

scholarly journals Beyond peroxisome proliferator-activated receptor γ signaling: the multi-facets of the antitumor effect of thiazolidinediones

2006 ◽  
Vol 13 (2) ◽  
pp. 401-413 ◽  
Author(s):  
J-R Weng ◽  
C-Y Chen ◽  
J J Pinzone ◽  
M D Ringel ◽  
C-S Chen
Keyword(s):  
Gene Expression ◽  
Anticancer Agents ◽  
Specific Antigen ◽  
Underlying Mechanism ◽  
Peroxisome Proliferator ◽  
Inhibitory Protein ◽  
Antitumor Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Bh3 Domain ◽  
B Cell Leukemia

Certain members of the thiazolidinedione (TZD) family of the peroxisome proliferator-activated receptor γ (PPARγ) agonists, such as troglitazone and ciglitazone, exhibit antitumor activities; however, the underlying mechanism remains inconclusive. Substantial evidence suggests that the antiproliferative effect of these TZD members in cancer cells is independent of PPARγ activation. To discern the role of PPARγ in the antitumor effects of TZDs, we have synthesized PPARγ-inactive TZD analogs which, although devoid of PPARγ activity, retain the ability to induce apoptosis with a potency equal to that of their parental TZDs in cancer cell lines with varying PPARγ expression status. Mechanistic studies from this and other laboratories have further suggested that troglitazone and ciglitazone mediate antiproliferative effects through a complexity of PPARγ-independent mechanisms. Evidence indicates that troglitazone and ciglitazone block BH3 domain-mediated interactions between the anti apoptotic Bcl-2 (B-cell leukemia/lymphoma 2) members Bcl-2/Bcl-xL and proapoptotic Bcl-2 members. Moreover, these TZDs facilitate the degradation of cyclin D1 and caspase-8-related FADD-like IL-l-converting enzyme (FLICE)-inhibitory protein through proteasome-mediated proteolysis, and down-regulate the gene expression of prostate-specific antigen gene expression by inhibiting androgen activation of the androgen response elements in the promoter region. More importantly, dissociation of the effects of TZDs on apoptosis from their original pharmacological activity (i.e. PPARγ activation) provides a molecular basis for the exploitation of these compounds to develop different types of molecularly targeted anticancer agents. These TZD-derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment.

Disruption of transforming growth factor-β signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-γ in rat hepatic stellate cells

2007 ◽  
Vol 292 (1) ◽  
pp. G113-G123 ◽  
Author(s):  
Shizhong Zheng ◽  
Anping Chen
Keyword(s):  
Gene Expression ◽  
Hepatic Stellate Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Gene Promoter ◽  
Stellate Cells ◽  
Transforming Growth Factor Β ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Activation of hepatic stellate cells (HSC), the major effectors of hepatic fibrogenesis, is coupled with sequential alterations in gene expression, including an increase in receptors for transforming growth factor-β (TGF-β) and a dramatic reduction in the peroxisome proliferator-activated receptor-γ (PPAR-γ). The relationship between them remains obscure. We previously demonstrated that curcumin induced gene expression of PPAR-γ in activated HSC, leading to reducing cell proliferation, inducing apoptosis and suppressing expression of extracellular matrix genes. The underlying molecular mechanisms are largely unknown. We recently observed that stimulation of PPAR-γ activation suppressed gene expression of TGF-β receptors in activated HSC, leading to the interruption of TGF-β signaling. This observation supported our assumption of an antagonistic relationship between PPAR-γ activation and TGF-β signaling in HSC. In this study, we further hypothesize that TGF-β signaling might negatively regulate gene expression of PPAR-γ in activated HSC. The present report demonstrates that exogenous TGF-β1 inhibits gene expression of PPAR-γ in activated HSC, which is eliminated by the pretreatment with curcumin likely by interrupting TGF-β signaling. Transfection assays further indicate that blocking TGF-β signaling by dominant negative type II TGF-β receptor increases the promoter activity of PPAR-γ gene. Promoter deletion assays, site-directed mutageneses, and gel shift assays localize two Smad binding elements (SBEs) in the PPAR-γ gene promoter, acting as curcumin response elements and negatively regulating the promoter activity in passaged HSC. The Smad3/4 protein complex specifically binds to the SBEs. Overexpression of Smad4 dose dependently eliminates the inhibitory effects of curcumin on the PPAR-γ gene promoter and TGF-β signaling. Taken together, these results demonstrate that the interruption of TGF-β signaling by curcumin induces gene expression of PPAR-γ in activated HSC in vitro. Our studies provide novel insights into the molecular mechanisms of curcumin in the induction of PPAR-γ gene expression and in the inhibition of HSC activation.

scholarly journals Regulation of IGFBP-2 expression during fasting

2015 ◽  
Vol 467 (3) ◽  
pp. 453-460 ◽  
Author(s):  
Hye Suk Kang ◽  
Mi-Young Kim ◽  
Seung-Jae Kim ◽  
Jae-Ho Lee ◽  
Yong-Deuk Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Promoter ◽  
Biological Action ◽  
Peroxisome Proliferator ◽  
Cultured Hepatocytes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Akt Phosphorylation ◽  
Primary Cultured Hepatocytes ◽  
Igf Binding ◽  
Responsive Element

Insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2), one of the most abundant circulating IGFBPs, is known to attenuate the biological action of IGF-1. Although the effect of IGFBP-2 in preventing metabolic disorders is well known, its regulatory mechanism remains unclear. In the present study, we demonstrated the transcriptional regulation of the Igfbp-2 gene by peroxisome-proliferator-activated receptor (PPAR) α in the liver. During fasting, both Igfbp-2 and PPARα expression levels were increased. Wy14643, a selective PPARα agonist, significantly induced Igfbp-2 gene expression in primary cultured hepatocytes. However, Igfbp-2 gene expression in Pparα null mice was not affected by fasting or Wy14643. In addition, through transient transfection and chromatin immunoprecipitation assay in fasted livers, we determined that PPARα bound to the putative PPAR-responsive element between −511 bp and −499 bp on the Igfbp-2 gene promoter, indicating that the Igfbp-2 gene transcription is activated directly by PPARα. To explore the role of PPARα in IGF-1 signalling, we treated primary cultured hepatocytes with Wy14643 and observed a decrease in the number of IGF-1 receptors (IGF-1Rs) and in Akt phosphorylation. No inhibition was observed in the hepatocytes isolated from Pparα null mice. These results suggest that PPARα controls IGF-1 signalling through the up-regulation of hepatic Igfbp-2 transcription during fasting and Wy14643 treatment.

scholarly journals Peroxisome Proliferator-activated Receptor α (PPARα) Induces PPARγ Coactivator 1α (PGC-1α) Gene Expression and Contributes to Thermogenic Activation of Brown Fat

2011 ◽  
Vol 286 (50) ◽  
pp. 43112-43122 ◽  
Author(s):  
Elayne Hondares ◽  
Meritxell Rosell ◽  
Julieta Díaz-Delfín ◽  
Yolanda Olmos ◽  
Maria Monsalve ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brown Fat ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

scholarly journals Bitter Orange (Citrus aurantium Linné) Improves Obesity by Regulating Adipogenesis and Thermogenesis through AMPK Activation

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1988 ◽  
Author(s):  
Park ◽  
Kim ◽  
Jung ◽  
Ahn ◽  
Kwak ◽  
...  
Keyword(s):  
Uncoupling Protein ◽  
Underlying Mechanism ◽  
Peroxisome Proliferator ◽  
Citrus Aurantium ◽  
Brown Adipocytes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Bitter Orange ◽  
Enhancer Binding Protein ◽  
Amp Activated Protein Kinase

Obesity is a global health threat. Herein, we evaluated the underlying mechanism of anti-obese features of bitter orange (Citrus aurantium Linné, CA). Eight-week-administration of CA in high fat diet-induced obese C57BL/6 mice resulted in a significant decrease of body weight, adipose tissue weight and serum cholesterol. In further in vitro studies, we observed decreased lipid droplets in CA-treated 3T3-L1 adipocytes. Suppressed peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein alpha indicated CA-inhibited adipogenesis. Moreover, CA-treated primary cultured brown adipocytes displayed increased differentiation associated with elevation of thermogenic factors including uncoupling protein 1 and PPARγ coactivator 1 alpha as well. The effects of CA in both adipocytes were abolished in AMP-activated protein kinase alpha (AMPKα)-suppressed environments, suggesting the anti-adipogenic and pro-thermogenic actions of CA were dependent on AMPKα pathway. In conclusion, our results suggest CA as a potential anti-obese agent which regulates adipogenesis and thermogenesis via AMPKα.

scholarly journals The differential effects of the timing of maternal nutrient restriction in the ovine placenta on glucocorticoid sensitivity, uncoupling protein 2, peroxisome proliferator-activated receptor-γ and cell proliferation

Reproduction ◽  
2009 ◽  
Vol 138 (3) ◽  
pp. 601-608 ◽  
Author(s):  
M Yiallourides ◽  
S P Sebert ◽  
V Wilson ◽  
D Sharkey ◽  
S M Rhind ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Fetal Growth ◽  
Uncoupling Protein ◽  
Nutrient Restriction ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Differential Effects ◽  
Glucocorticoid Sensitivity ◽  
Ovine Placenta

Nutrient restriction (NR) during critical windows of pregnancy has differential effects on placento-fetal growth and development. Our study, therefore, investigated developmental and metabolic adaptations within the ovine placenta following NR at different critical windows during the first 110 days of gestation (term=147 days). Thus, the effects of NR on cell proliferation, glucocorticoid sensitivity, IGF1 and 2 receptor, peroxisome proliferator-activated receptor γ (PPARG), and uncoupling protein (UCP)2 gene expression in the placenta were examined. Singleton bearing sheep (n=4–8 per group) were fed either 100% of their total metabolizable energy requirements throughout the study or 50% of this amount between 0–30, 31–65, 66–110, and 0–110 days gestation. A significant reduction in cell proliferation and increased gene expression for the glucocorticoid and IGF2 receptors, PPARG, and UCP2 were detected in placentae sampled from mothers who were nutrient restricted between days 66 and 110 of gestation, only, relative to controls. This window of gestation coincides with the maximum placental growth and the start of exponential growth of the fetus when there are substantially increased metabolic demands on the placenta compared with earlier in gestation. Consequently, increased glucocorticoid sensitivity and suppressed IGF2 action could contribute to a switch in the placenta from proliferation to differentiation, thereby improving its nutrient transfer capacity. Upregulation of PPARG and UCP2 would promote placental fatty acid metabolism thereby limiting glucose utilization. These compensatory placental responses may serve to maintain fetal growth but could result in adverse adaptations such as the early onset of the metabolic syndrome in later life.

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