scholarly journals Glucocorticoid Receptor Accelerates, but Is Dispensable for, Adipogenesis

2016 ◽  
Vol 37 (2) ◽  
Author(s):  
Young-Kwon Park ◽  
Kai Ge
Keyword(s):  
Glucocorticoid Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Enhancer Binding Protein ◽  
Brown Adipose ◽  
Histone H3k27 ◽  
Synthetic Ligand ◽  
Adipose Tissue Development ◽  
Induction Of Differentiation

ABSTRACT Dexamethasone (DEX), a synthetic ligand for glucocorticoid receptor (GR), is routinely used to stimulate adipogenesis in culture. GR-depleted preadipocytes show adipogenesis defects 1 week after induction of differentiation. However, it has remained unclear whether GR is required for adipogenesis in vivo. By deleting GR in precursors of brown adipocytes, we found unexpectedly that GR is dispensable for brown adipose tissue development in mice. In culture, GR-deficient primary or immortalized white and brown preadipocytes showed severely delayed adipogenesis 1 week after induction of differentiation. However, when differentiation was extended to 3 weeks, GR-deficient preadipocytes showed levels of adipogenesis marker expression and lipid accumulation similar to those of the wild-type cells, indicating that DEX-bound GR accelerates, but is dispensable for, adipogenesis. Consistently, DEX accelerates, but is dispensable for, adipogenesis in culture. We show that DEX-bound GR accelerates adipogenesis by directly promoting the expression of adipogenic transcription factors CCAAT/enhancer-binding protein alpha (C/EBPα), C/EBPβ, C/EBPδ, KLF5, KLF9, and peroxisome proliferator-activated receptor γ (PPARγ) in the early phase of differentiation. Mechanistically, DEX-bound GR recruits histone H3K27 acetyltransferase CBP to promote activation of C/EBPβ-primed enhancers of adipogenic genes. These results clarify the role of GR in adipogenesis in vivo and demonstrate that DEX-mediated activation of GR accelerates, but is dispensable for, adipogenesis.

scholarly journals Distinct Roles of Transcription Factors KLF4, Krox20, and Peroxisome Proliferator-Activated Receptor γ in Adipogenesis

2016 ◽  
Vol 37 (2) ◽  
Author(s):  
Young-Kwon Park ◽  
Limin Wang ◽  
Anne Giampietro ◽  
Binbin Lai ◽  
Ji-Eun Lee ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Conditional Knockout ◽  
Peroxisome Proliferator ◽  
Preadipocyte Differentiation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Brown Adipose ◽  
Culture Models ◽  
Adipose Tissue Development ◽  
Cell Culture Models

ABSTRACT Much of our knowledge on adipogenesis comes from cell culture models of preadipocyte differentiation. Adipogenesis is induced by treating confluent preadipocytes with the adipogenic cocktail, which activates transcription factors (TFs) glucocorticoid receptor (GR) and CREB within minutes and increases expression of TFs C/EBPβ, C/EBPδ, KLF4, and Krox20 within hours. All of these TFs have been shown to be capable of promoting adipogenesis in culture when they are overexpressed. However, it has remained unclear whether endogenous KLF4 and Krox20 are required for adipogenesis in culture and in vivo. Using conditional knockout mice and derived white and brown preadipocytes, we show that endogenous KLF4 and Krox20 are dispensable for adipogenesis in culture and for brown adipose tissue development in mice. In contrast, the master adipogenic TF peroxisome proliferator-activated receptor γ (PPARγ) is essential. These results challenge the existing model on transcriptional regulation in the early phase of adipogenesis and highlight the need of studying adipogenesis in vivo.

Tissue-specific postprandial clearance is the major determinant of PPARγ-induced triglyceride lowering in the rat

2009 ◽  
Vol 296 (1) ◽  
pp. R57-R66 ◽  
Author(s):  
Mathieu Laplante ◽  
William T. Festuccia ◽  
Geneviève Soucy ◽  
Pierre-Gilles Blanchard ◽  
Alexandra Renaud ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Peroxisome Proliferator ◽  
Lipid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Fatty Acid Binding ◽  
Tissue Specific ◽  
Fat Depots ◽  
Relative Contribution ◽  
Brown Adipose

Peroxisome proliferator-activated receptor-γ (PPARγ) agonism potently reduces circulating triglycerides (TG) in rodents and more modestly so in humans. This study aimed to quantify in vivo the relative contribution of hepatic VLDL-TG secretion and tissue-specific TG clearance to such action. Rats were fed an obesogenic diet, treated with the PPARγ full agonist COOH (30 mg·kg−1·day−1) for 3 wk, and studied in both the fasted and refed (fat-free) states. Hepatic VLDL-TG secretion rate was not affected by chronic COOH in the fasted state and was only modestly decreased (−30%) in refed rats. In contrast, postprandial VLDL-TG clearance was increased 2.6-fold by COOH, which concomitantly stimulated adipose tissue TG-derived lipid uptake and one of its major determinants, lipoprotein lipase (LPL) activity, in a highly depot-specific manner. TG-derived lipid uptake and LPL were indeed strongly increased in subcutaneous inguinal white adipose tissue and in brown adipose tissue, independently of the nutritional state, whereas of the three visceral fat depots examined (epididymal, retroperitoneal, mesenteric) only the latter responded consistently to COOH. Robust correlations (0.5 < r < 0.9) were observed between TG-derived lipid uptake and LPL in adipose tissues. The agonist did not increase LPL in muscle, and its enhancing action on postprandial muscle lipid uptake appeared to be mediated by post-LPL processes involving increased expression of fatty acid binding/transport proteins (aP2, likely in infiltrated adipocytes, FAT/CD36, and FATP-1). The study establishes in a diet-induced obesity model the major contribution of lipid uptake by specific, metabolically safe adipose depots to the postprandial hypotriglyceridemic action of PPARγ agonism, and suggests a key role for LPL therein.

scholarly journals Temporal recruitment of CCAAT/enhancer-binding proteins to early and late adipogenic promoters in vivo

2006 ◽  
Vol 36 (1) ◽  
pp. 139-151 ◽  
Author(s):  
N Salma ◽  
H Xiao ◽  
A N Imbalzano
Keyword(s):  
Dna Binding ◽  
Chromatin Immunoprecipitation ◽  
Binding Capacity ◽  
Regulatory Sequences ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Enhancer Binding Protein ◽  
Kinetics Of

The CCAAT/enhancer-binding protein (C/EBP) family of transcriptional regulators is critically important for the activation of adipogenic genes during differentiation. The C/EBPβ and δ isoforms are rapidly induced upon adipocyte differentiation and are responsible for activating the adipogenic regulators C/EBPα and peroxisome proliferator activated receptor (PPAR)γ2, which together activate the majority of genes expressed in differentiating adipocytes. However, mitosis is required following the induction of adipogenesis, and the activation of C/EBPα and PPARγ2 gene expression is delayed until cell division is underway. Previous studies have used electromobility shift assays to suggest that this delay is due, at least in part, to a delay between the induction of C/EBPβ protein levels and the acquisition of DNA binding capacity by C/EBPβ. Here we used in vivo chromatin immunoprecipitation analysis of the C/EBPα, PPARγ2, resistin, adiponectin, and leptin promoters to examine the kinetics of C/EBP protein binding to adipogenic genes in differentiating cells. In contrast to prior studies, we determined that C/EBPβ and δ were bound to endogenous regulatory sequences controlling the expression of these genes within 1–4 h of adipogenic induction. These results indicated that C/EBPβ and δ bind not only to genes that are induced early in the adipogenic process but also to genes that are induced much later during differentiation, without a delay between induction of C/EBP protein levels and DNA binding by these proteins. We also showed that each of the genes examined undergoes a transition in vivo from early occupancy by C/EBPβ and δ to occupancy by C/EBPα at times that correlate with the induction of C/EBPα protein levels, demonstrating the generality of the transition during adipogenesis and indicating that the binding of specific C/EBP isoforms does not correlate with timing of expression from each gene. We have concluded that C/EBP family members bind to adipogenic genes in vivo in a manner that follows the induction of C/EBP protein synthesis.

scholarly journals MLL3/MLL4-Associated PAGR1 Regulates Adipogenesis by Controlling Induction of C/EBPβ and C/EBPδ

2020 ◽  
Vol 40 (17) ◽  
Author(s):  
Ji-Eun Lee ◽  
Young-Wook Cho ◽  
Chu-Xia Deng ◽  
Kai Ge
Keyword(s):  
Transcription Factors ◽  
Muscle Development ◽  
Critical Role ◽  
Ectopic Expression ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Histone Methyltransferases ◽  
Brown Adipose ◽  
Phosphorylated Creb

ABSTRACT Transcription factors C/EBPβ and C/EBPδ are induced within hours after initiation of adipogenesis in culture. They directly promote the expression of master adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα and are required for adipogenesis in vivo. However, the mechanism that controls the induction of C/EBPβ and C/EBPδ remains elusive. We previously showed that histone methyltransferases MLL3/MLL4 and associated PTIP are required for the induction of PPARγ and C/EBPα during adipogenesis. Here, we show MLL3/MLL4/PTIP-associated protein PAGR1 (also known as PA1) cooperates with phosphorylated CREB and ligand-activated glucocorticoid receptor to directly control the induction of C/EBPβ and C/EBPδ in the early phase of adipogenesis. Deletion of Pagr1 in white and brown preadipocytes prevents the induction of C/EBPβ and C/EBPδ and leads to severe defects in adipogenesis. Adipogenesis defects in PAGR1-deficient cells can be rescued by the ectopic expression of C/EBPβ or PPARγ. Finally, the deletion of Pagr1 in Myf5+ precursor cells impairs brown adipose tissue and muscle development. Thus, by controlling the induction of C/EBPβ and C/EBPδ, PAGR1 plays a critical role in adipogenesis.

scholarly journals Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
KyeongJin Kim ◽  
Jin Ku Kang ◽  
Young Hoon Jung ◽  
Sang Bae Lee ◽  
Raffaela Rametta ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Whole Body ◽  
Acid Oxidation ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Ph Domain ◽  
Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

scholarly journals The lipid-lowering drug fenofibrate combined with si-HOTAIR can effectively inhibit the proliferation of gliomas

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei Zhu ◽  
Hongyang Zhao ◽  
Fenfen Xu ◽  
Bin Huang ◽  
Xiaojing Dai ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Glioma Cells ◽  
Lipid Lowering ◽  
Fibric Acid Derivative ◽  
Peroxisome Proliferator ◽  
Glioma Invasion ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lncrna Hotair

Abstract Background Fenofibrate is a fibric acid derivative known to have a lipid-lowering effect. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcription activation has been shown to play an important role in the malignant progression of gliomas, the underlying mechanisms are poorly understood. Methods In this study, we analyzed TCGA database and found that there was a significant negative correlation between the long noncoding RNA (lncRNA) HOTAIR and PPARα. Then, we explored the molecular mechanism by which lncRNA HOTAIR regulates PPARα in cell lines in vitro and in a nude mouse glioma model in vivo and explored the effect of the combined application of HOTAIR knockdown and fenofibrate treatment on glioma invasion. Results For the first time, it was shown that after knockdown of the expression of HOTAIR in gliomas, the expression of PPARα was significantly upregulated, and the invasion and proliferation ability of gliomas were obviously inhibited. Then, glioma cells were treated with both the PPARα agonist fenofibrate and si-HOTAIR, and the results showed that the proliferation and invasion of glioma cells were significantly inhibited. Conclusions Our results suggest that HOTAIR can negatively regulate the expression of PPARα and that the combination of fenofibrate and si-HOTAIR treatment can significantly inhibit the progression of gliomas. This introduces new ideas for the treatment of gliomas.

scholarly journals The Novel Role of PGC1α in Bone Metabolism

2021 ◽  
Vol 22 (9) ◽  
pp. 4670
Author(s):  
Cinzia Buccoliero ◽  
Manuela Dicarlo ◽  
Patrizia Pignataro ◽  
Francesco Gaccione ◽  
Silvia Colucci ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Osteoblastic Differentiation ◽  
In Vivo Studies ◽  
Peroxisome Proliferator ◽  
Sirtuin 3 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Increased Risk

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.

scholarly journals The Demethoxy Derivatives of Curcumin Exhibit Greater Differentiation Suppression in 3T3-L1 Adipocytes Than Curcumin: A Mechanistic Study of Adipogenesis and Molecular Docking

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1025
Author(s):  
Ahmed Alalaiwe ◽  
Jia-You Fang ◽  
Hsien-Ju Lee ◽  
Chun-Hui Chiu ◽  
Ching-Yun Hsu
Keyword(s):  
Molecular Docking ◽  
Fatty Acid Synthase ◽  
Structural Similarity ◽  
Mechanistic Study ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Enhancer Binding Protein ◽  
Underlying Mechanisms ◽  
Amp Activated Protein Kinase

Curcumin is a known anti-adipogenic agent for alleviating obesity and related disorders. Comprehensive comparisons of the anti-adipogenic activity of curcumin with other curcuminoids is minimal. This study compared adipogenesis inhibition with curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC), and their underlying mechanisms. We differentiated 3T3-L1 cells in the presence of curcuminoids, to determine lipid accumulation and triglyceride (TG) production. The expression of adipogenic transcription factors and lipogenic proteins was analyzed by Western blot. A significant reduction in Oil red O (ORO) staining was observed in the cells treated with curcuminoids at 20 μM. Inhibition was increased in the order of curcumin < DMC < BDMC. A similar trend was observed in the detection of intracellular TG. Curcuminoids suppressed differentiation by downregulating the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), leading to the downregulation of the lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). AMP-activated protein kinase α (AMPKα) phosphorylation was also activated by BDMC. Curcuminoids reduced the release of proinflammatory cytokines and leptin in 3T3-L1 cells in a dose-dependent manner, with BDMC showing the greatest potency. BDMC at 20 μM significantly decreased leptin by 72% compared with differentiated controls. Molecular docking computation indicated that curcuminoids, despite having structural similarity, had different interaction positions to PPARγ, C/EBPα, and ACC. The docking profiles suggested a possible interaction of curcuminoids with C/EBPα and ACC, to directly inhibit their expression.

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