Suppression of adipocyte differentiation by Cordyceps militaris through activation of the aryl hydrocarbon receptor

2008 ◽  
Vol 295 (4) ◽  
pp. E859-E867 ◽  
Author(s):  
Tsuyoshi Shimada ◽  
Nobuhiko Hiramatsu ◽  
Ayumi Kasai ◽  
Mai Mukai ◽  
Maro Okamura ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Mammalian Cells ◽  
Adipocyte Differentiation ◽  
Biological Activities ◽  
Cordyceps Militaris ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Monocyte Chemoattractant Protein 1 ◽  
Aryl Hydrocarbon ◽  
Wide Range

Mycelial extracts have a wide range of biological activities that modulate functions of mammalian cells. In this report, we sought to identify antiadipogenic mycelia with the use of 3T3-L1 cells and found that the extract of Cordyceps militaris exclusively suppressed differentiation of 3T3-L1 preadipocytes into mature adipocytes without affecting cell viability. This inhibitory effect was dose dependent, reversible, and associated with 1) a decrease in lipid accumulation, 2) blunted induction of adipocyte markers including adiponectin, peroxisome proliferator-activated receptor-γ, and CCAAT/enhancer binding protein-α, and 3) sustained expression of a preadipocyte marker, monocyte chemoattractant protein-1. C. militaris also significantly decreased accumulation of lipid and hypertrophy in mature adipocytes and preserved their response to insulin (phosphorylation of Akt) during prolonged culture. Subsequent experiments revealed that C. militaris has the potential to activate the aryl hydrocarbon receptor (AhR). In 3T3-L1 cells, treatment with AhR agonists including benzo[ a]pyrene and 3-methylcholanthrene reproduced the antiadipogenic effect of C. militaris. Furthermore, dominant-negative inhibition of AhR abrogated the suppressive effect of C. militaris on adipocyte differentiation. These results suggest that C. militaris has the potential to interfere with adipocyte differentiation through activation of AhR.

Dual suppression of adipogenesis by cigarette smoke through activation of the aryl hydrocarbon receptor and induction of endoplasmic reticulum stress

2009 ◽  
Vol 296 (4) ◽  
pp. E721-E730 ◽  
Author(s):  
Tsuyoshi Shimada ◽  
Nobuhiko Hiramatsu ◽  
Kunihiro Hayakawa ◽  
Shuhei Takahashi ◽  
Ayumi Kasai ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Aryl Hydrocarbon Receptor ◽  
Cigarette Smoke ◽  
Molecular Mechanisms ◽  
Adipocyte Differentiation ◽  
Suppressive Effect ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Aryl Hydrocarbon

Cigarette smoking decreases body weight, whereas molecular mechanisms underlying this phenomenon have not been elucidated. In this report, we investigated regulation of adipogenesis by cigarette smoke and involvement of aryl hydrocarbon receptor (AhR) and endoplasmic reticulum (ER) stress. We found that cigarette smoke extract (CSE) inhibited differentiation of preadipocytes into adipocytes dose dependently. It was associated with a decrease in lipid accumulation, blunted expression of adipocyte markers (adiponectin, PPAR-γ, and C/EBPα), and sustained expression of a preadipocyte marker MCP-1. CSE markedly induced activation of AhR, and AhR agonists (2,3,7,8-tetrachlorodibenzo- p-dioxin, benzo[ a]pyrene and 3-methylcholanthrene) reproduced the inhibitory effect of CSE on adipocyte differentiation. Furthermore, knockout of the AhR gene or blockade of AhR by a dominant-negative mutant attenuated the suppressive effects of CSE on adipocyte differentiation. We also found that CSE induced ER stress in preadipocytes, and ER stress inducers (thapsigargin, tunicamycin, and A23187) reproduced the suppressive effect of CSE on the differentiation of preadipocytes. Interestingly, AhR agonists did not cause ER stress, and ER stress inducers did not activate AhR. These results suggested that cigarette smoke has the potential to inhibit adipocyte differentiation via dual, independent mechanisms, i.e., through activation of the AhR pathway and induction of the unfolded protein response.

Specificity of Smad Signaling during Primitive Erythropoiesis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2785-2785
Author(s):  
Brian T. Zafonte ◽  
Tara L. Huber ◽  
Gordon Keller ◽  
Todd Evans
Keyword(s):  
Embryoid Body ◽  
Biological Activities ◽  
Es Cells ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cell ◽  
Dominant Negative ◽  
Hematopoietic Progenitors ◽  
Transcript Levels ◽  
Wide Range ◽  
Primitive Erythropoiesis

Abstract Bone morphogenetic proteins (BMPs) comprise a sub-family of TGF-beta-like molecules that exert a wide range of biological activities during development, and are essential for normal hematopoiesis. However, the precise stage in development that BMP signaling regulates hematopoiesis is not defined. Three proteins, Smad1, Smad5, and Smad8 transmit BMP signals to the nucleus to activate the expression of hematopoietic-specific transcription factors. These Smads are homologous in their sequences, and appear to be regulated similarly, however their specificity in regulating hematopoiesis remains undefined. Although Smad proteins are regulated post-translationally, their expression is also under transcriptional control during development. We examined the specificity of Smad1/5/8 activity in the context of primitive erythropoiesis, using the mouse embryonic stem cell /embryoid body (ES/EB) system. We exploited ES cells with GFP targeted to the brachyury locus, in order to identify specific sub-sets of progenitors. Smad1 transcript levels are initially upregulated as ES cells become fated to mesoderm and hematopoietic progenitors, but the levels are significantly decreased in cells derived from differentiating primitive erythroid colonies. In contrast, Smad5 transcript levels show the opposite profile, being more correlated with erythroid differentiation. To directly assess the role of these Smads during erythropoiesis, their activity is being manipulated in ES cells during the commitment phases of embryonic hematopoiesis. For this purpose, inducible ES cell lines were generated capable of forcing the expression of wildtype Smad1 or Smad5, or a dominant-negative isoform of Smad5, at any stage of ES/EB development. Colony assays were used to analyze quantitatively the hematopoietic potential of these cells. Forced expression of Smad1 results in a marked increase in primitive red blood cell colony formation as compared to control ES cells. Maintenance of Smad1 expression does not appear to inhibit terminal differentiation. Based on a time-study of the induction, the effect on erythoid colonies could be due to expansion of earlier progenitors. Current experiments using the in vitro blast assay are examining the direct effect of Smad1 expression on earlier (hemangioblast) development. This data, and analogous analyses of cells induced to express Smad5 or the dominant-negative Smad isoform are in progress and will be presented. These studies should facilitate our understanding of the specificity of BMP-regulated Smads during commitment and differentiation of embryonic stem cells and hematopoietic progenitors.

scholarly journals Effects of Baccharin Isolated from Brazilian Green Propolis on Adipocyte Differentiation and Hyperglycemia in ob/ob Diabetic Mice

2021 ◽  
Vol 22 (13) ◽  
pp. 6954
Author(s):  
Akio Watanabe ◽  
Marília Oliveira de Almeida ◽  
Yusuke Deguchi ◽  
Ryuzo Kozuka ◽  
Caroline Arruda ◽  
...  
Keyword(s):  
Target Genes ◽  
Adipocyte Differentiation ◽  
Biological Activities ◽  
Intraperitoneal Administration ◽  
Peroxisome Proliferator ◽  
Cinnamic Acid Derivative ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Levels ◽  
Glycerol 3 Phosphate Dehydrogenase ◽  
Brazilian Green Propolis

Propolis is a honeybee product with various biological activities, including antidiabetic effects. We previously reported that artepillin C, a prenylated cinnamic acid derivative isolated from Brazilian green propolis, acts as a peroxisome proliferator-activated receptor γ (PPARγ) ligand and promotes adipocyte differentiation. In this study, we examined the effect of baccharin, another major component of Brazilian green propolis, on adipocyte differentiation. The treatment of mouse 3T3-L1 preadipocytes with baccharin resulted in increased lipid accumulation, cellular triglyceride levels, glycerol-3-phosphate dehydrogenase activity, and glucose uptake. The mRNA expression levels of PPARγ and its target genes were also increased by baccharin treatment. Furthermore, baccharin enhanced PPARγ-dependent luciferase activity, suggesting that baccharin promotes adipocyte differentiation via PPARγ activation. In diabetic ob/ob mice, intraperitoneal administration of 50 mg/kg baccharin significantly improved blood glucose levels. Our results suggest that baccharin has a hypoglycemic effect on glucose metabolic disorders, such as type 2 diabetes mellitus.

scholarly journals Recruitment of the NCoA/SRC-1/p160 Family of Transcriptional Coactivators by the Aryl Hydrocarbon Receptor/Aryl Hydrocarbon Receptor Nuclear Translocator Complex

2002 ◽  
Vol 22 (12) ◽  
pp. 4319-4333 ◽  
Author(s):  
Timothy V. Beischlag ◽  
Song Wang ◽  
David W. Rose ◽  
Joseph Torchia ◽  
Suzanne Reisz-Porszasz ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Reporter Gene ◽  
Transcriptional Activation ◽  
Mammalian Cells ◽  
Luciferase Reporter ◽  
Pas Domain ◽  
Transactivation Domain ◽  
Aryl Hydrocarbon ◽  
Transcriptional Coactivators ◽  
Gene Assay

ABSTRACT The aryl hydrocarbon receptor complex heterodimeric transcription factor, comprising the basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) proteins, mediates the toxic effects of TCDD (2,3,7,8 tetrachlorodibenzo-p-dioxin). The molecular events underlying TCDD-inducible gene activation, beyond the activation of the AHRC, are poorly understood. The SRC-1/NCoA-1, NCoA-2/GRIP-1/TIF-2, and p/CIP/AIB/ACTR proteins have been shown to act as mediators of transcriptional activation. In this report, we demonstrate that SRC-1, NCoA-2, and p/CIP are capable of independently enhancing TCDD-dependent induction of a luciferase reporter gene by the AHR/ARNT dimer. Furthermore, injection of anti-SRC-1 or anti-p/CIP immunoglobulin G into mammalian cells abolishes the transcriptional activity of a TCDD-dependent reporter gene. We demonstrate by coimmunoprecipitation and by a reporter gene assay that SRC-1 and NCoA-2 but not p/CIP are capable of interacting with ARNT in vivo after transient transfection into mammalian cells, while AHR is capable of interacting with all three coactivators. We confirm the interactions of ARNT and AHR with SRC-1 with immunocytochemical techniques. Furthermore, SRC-1, NCoA-2, and p/CIP all associate with the CYP1A1 enhancer region in a TCDD-dependent fashion, as demonstrated by chromatin immunoprecipitation assays. We demonstrate by yeast two-hybrid, glutathione S-transferase pulldown, and mammalian reporter gene assays that ARNT requires its helix 2 domain but not its transactivation domain to interact with SRC-1. This indicates a novel mechanism of action for SRC-1. SRC-1 does not require its bHLH-PAS domain to interact with ARNT or AHR, but utilizes distinct domains proximal to its p300/CBP interaction domain. Taken together, these data support a role for the SRC family of transcriptional coactivators in TCDD-dependent gene regulation.

scholarly journals Deletion of the Aryl Hydrocarbon Receptor-associated Protein 9 Leads to Cardiac Malformation and Embryonic Lethality

2007 ◽  
Vol 282 (49) ◽  
pp. 35924-35932 ◽  
Author(s):  
Bernice C. Lin ◽  
Ruth Sullivan ◽  
Youngsook Lee ◽  
Susan Moran ◽  
Edward Glover ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Cardiac Development ◽  
Physiological Role ◽  
Homozygous Deletion ◽  
Embryonic Lethality ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Associated Protein ◽  
Aryl Hydrocarbon

The aryl hydrocarbon receptor-associated protein 9, ARA9 (also known as XAP2 or AIP1), is a chaperone that is found in complexes with certain xenobiotic receptors, such as the aryl hydrocarbon receptor (AHR) and the peroxisome proliferator-activated receptor α (PPARα). In an effort to better understand the physiological role of ARA9 outside of its role in xenobiotic signal transduction, we generated a null allele at the Ara9 locus in mice. Mice with a homozygous deletion of this gene die at various time points throughout embryonic development. Embryonic lethality is accompanied by decreased blood flow to head and limbs, as well as a range of heart deformations, including double outlet right ventricle, ventricular-septal defects, and pericardial edema. The early cardiovascular defects observed in Ara9-null mice suggest an essential role for the ARA9 protein in cardiac development. The observation that the developmental aberrations in Ara9-null mice are distinct from those observed for disrupted alleles at Ahr or Pparα indicates that the role of ARA9 in cardiac development is independent of its interactions with its known xenobiotic receptor partners.

scholarly journals Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1158-1165 ◽  
Author(s):  
B. Paige Lawrence ◽  
Michael S. Denison ◽  
Hermann Novak ◽  
Beth A. Vorderstrasse ◽  
Nathalie Harrer ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Aryl Hydrocarbon Receptor ◽  
Lung Inflammation ◽  
Dominant Negative ◽  
Low Molecular Weight ◽  
Aryl Hydrocarbon ◽  
Allergic Lung Inflammation ◽  
Anti Inflammatory

Abstract VAF347 is a low-molecular-weight compound that inhibits allergic lung inflammation in vivo. This effect is likely the result of a block of dendritic cell (DC) function to generate proinflammatory T-helper (Th) cells because VAF347 inhibits interleukin (IL)–6, CD86, and human leukocyte antigen (HLA)–DR expression by human monocyte-derived DC, 3 relevant molecules for Th-cell generation. Here we demonstrate that VAF347 interacts with the aryl hydrocarbon receptor (AhR) protein, resulting in activation of the AhR signaling pathway. Functional AhR is responsible for the biologic activity of VAF347 because (1) other AhR agonists display an identical activity profile in vitro, (2) gene silencing of wild-type AhR expression or forced overexpression of a trans-dominant negative AhR ablates VAF347 activity to inhibit cytokine induced IL-6 expression in a human monocytic cell line, and (3) AhR-deficient mice are resistant to the compound's ability to block allergic lung inflammation in vivo. These data identify the AhR protein as key molecular target of VAF347 and its essential role for mediating the anti-inflammatory effects of the compound in vitro and in vivo.

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