PPARγ antagonists induce aromatase transcription in adipose tissue cultures

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

PPARγ antagonists induce aromatase transcription in adipose tissue cultures. / Ardenkjær-Skinnerup, Jacob; Saar, Daniel; Petersen, Patricia S.S.; Pedersen, Mikael; Svingen, Terje; Kragelund, Birthe B.; Hadrup, Niels; Ravn-Haren, Gitte; Emanuelli, Brice; Brown, Kristy A.; Vogel, Ulla.

In: Biochemical Pharmacology, Vol. 222, 116095, 2024.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Ardenkjær-Skinnerup, J, Saar, D, Petersen, PSS, Pedersen, M, Svingen, T, Kragelund, BB, Hadrup, N, Ravn-Haren, G, Emanuelli, B, Brown, KA & Vogel, U 2024, 'PPARγ antagonists induce aromatase transcription in adipose tissue cultures', Biochemical Pharmacology, vol. 222, 116095. https://doi.org/10.1016/j.bcp.2024.116095

APA

Ardenkjær-Skinnerup, J., Saar, D., Petersen, P. S. S., Pedersen, M., Svingen, T., Kragelund, B. B., Hadrup, N., Ravn-Haren, G., Emanuelli, B., Brown, K. A., & Vogel, U. (2024). PPARγ antagonists induce aromatase transcription in adipose tissue cultures. Biochemical Pharmacology, 222, [116095]. https://doi.org/10.1016/j.bcp.2024.116095

Vancouver

Ardenkjær-Skinnerup J, Saar D, Petersen PSS, Pedersen M, Svingen T, Kragelund BB et al. PPARγ antagonists induce aromatase transcription in adipose tissue cultures. Biochemical Pharmacology. 2024;222. 116095. https://doi.org/10.1016/j.bcp.2024.116095

Author

Ardenkjær-Skinnerup, Jacob ; Saar, Daniel ; Petersen, Patricia S.S. ; Pedersen, Mikael ; Svingen, Terje ; Kragelund, Birthe B. ; Hadrup, Niels ; Ravn-Haren, Gitte ; Emanuelli, Brice ; Brown, Kristy A. ; Vogel, Ulla. / PPARγ antagonists induce aromatase transcription in adipose tissue cultures. In: Biochemical Pharmacology. 2024 ; Vol. 222.

Bibtex

@article{9206bf7bc7394be595971ea101a413c0,
title = "PPARγ antagonists induce aromatase transcription in adipose tissue cultures",
abstract = "Aromatase is the rate-limiting enzyme in the biosynthesis of estrogens and a key risk factor for hormone receptor-positive breast cancer. In postmenopausal women, estrogens synthesized in adipose tissue promotes the growth of estrogen receptor positive breast cancers. Activation of peroxisome proliferator-activated receptor gamma (PPARγ) in adipose stromal cells (ASCs) leads to decreased expression of aromatase and differentiation of ASCs into adipocytes. Environmental chemicals can act as antagonists of PPARγ and disrupt its function. This study aimed to test the hypothesis that PPARγ antagonists can promote breast cancer by stimulating aromatase expression in human adipose tissue. Primary cells and explants from human adipose tissue as well as A41hWAT, C3H10T1/2, and H295R cell lines were used to investigate PPARγ antagonist-stimulated effects on adipogenesis, aromatase expression, and estrogen biosynthesis. Selected antagonists inhibited adipocyte differentiation, preventing the adipogenesis-associated downregulation of aromatase. NMR spectroscopy confirmed direct interaction between the potent antagonist DEHPA and PPARγ, inhibiting agonist binding. Short-term exposure of ASCs to PPARγ antagonists upregulated aromatase only in differentiated cells, and a similar effect could be observed in human breast adipose tissue explants. Overexpression of PPARG with or without agonist treatment reduced aromatase expression in ASCs. The data suggest that environmental PPARγ antagonists regulate aromatase expression in adipose tissue through two mechanisms. The first is indirect and involves inhibition of adipogenesis, while the second occurs more acutely.",
keywords = "Adipogenesis, Adipose tissue, Aromatase, Breast cancer, Endocrine disruption, PPARγ",
author = "Jacob Ardenkj{\ae}r-Skinnerup and Daniel Saar and Petersen, {Patricia S.S.} and Mikael Pedersen and Terje Svingen and Kragelund, {Birthe B.} and Niels Hadrup and Gitte Ravn-Haren and Brice Emanuelli and Brown, {Kristy A.} and Ulla Vogel",
note = "Publisher Copyright: {\textcopyright} 2024 The Authors",
year = "2024",
doi = "10.1016/j.bcp.2024.116095",
language = "English",
volume = "222",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - PPARγ antagonists induce aromatase transcription in adipose tissue cultures

AU - Ardenkjær-Skinnerup, Jacob

AU - Saar, Daniel

AU - Petersen, Patricia S.S.

AU - Pedersen, Mikael

AU - Svingen, Terje

AU - Kragelund, Birthe B.

AU - Hadrup, Niels

AU - Ravn-Haren, Gitte

AU - Emanuelli, Brice

AU - Brown, Kristy A.

AU - Vogel, Ulla

N1 - Publisher Copyright: © 2024 The Authors

PY - 2024

Y1 - 2024

N2 - Aromatase is the rate-limiting enzyme in the biosynthesis of estrogens and a key risk factor for hormone receptor-positive breast cancer. In postmenopausal women, estrogens synthesized in adipose tissue promotes the growth of estrogen receptor positive breast cancers. Activation of peroxisome proliferator-activated receptor gamma (PPARγ) in adipose stromal cells (ASCs) leads to decreased expression of aromatase and differentiation of ASCs into adipocytes. Environmental chemicals can act as antagonists of PPARγ and disrupt its function. This study aimed to test the hypothesis that PPARγ antagonists can promote breast cancer by stimulating aromatase expression in human adipose tissue. Primary cells and explants from human adipose tissue as well as A41hWAT, C3H10T1/2, and H295R cell lines were used to investigate PPARγ antagonist-stimulated effects on adipogenesis, aromatase expression, and estrogen biosynthesis. Selected antagonists inhibited adipocyte differentiation, preventing the adipogenesis-associated downregulation of aromatase. NMR spectroscopy confirmed direct interaction between the potent antagonist DEHPA and PPARγ, inhibiting agonist binding. Short-term exposure of ASCs to PPARγ antagonists upregulated aromatase only in differentiated cells, and a similar effect could be observed in human breast adipose tissue explants. Overexpression of PPARG with or without agonist treatment reduced aromatase expression in ASCs. The data suggest that environmental PPARγ antagonists regulate aromatase expression in adipose tissue through two mechanisms. The first is indirect and involves inhibition of adipogenesis, while the second occurs more acutely.

AB - Aromatase is the rate-limiting enzyme in the biosynthesis of estrogens and a key risk factor for hormone receptor-positive breast cancer. In postmenopausal women, estrogens synthesized in adipose tissue promotes the growth of estrogen receptor positive breast cancers. Activation of peroxisome proliferator-activated receptor gamma (PPARγ) in adipose stromal cells (ASCs) leads to decreased expression of aromatase and differentiation of ASCs into adipocytes. Environmental chemicals can act as antagonists of PPARγ and disrupt its function. This study aimed to test the hypothesis that PPARγ antagonists can promote breast cancer by stimulating aromatase expression in human adipose tissue. Primary cells and explants from human adipose tissue as well as A41hWAT, C3H10T1/2, and H295R cell lines were used to investigate PPARγ antagonist-stimulated effects on adipogenesis, aromatase expression, and estrogen biosynthesis. Selected antagonists inhibited adipocyte differentiation, preventing the adipogenesis-associated downregulation of aromatase. NMR spectroscopy confirmed direct interaction between the potent antagonist DEHPA and PPARγ, inhibiting agonist binding. Short-term exposure of ASCs to PPARγ antagonists upregulated aromatase only in differentiated cells, and a similar effect could be observed in human breast adipose tissue explants. Overexpression of PPARG with or without agonist treatment reduced aromatase expression in ASCs. The data suggest that environmental PPARγ antagonists regulate aromatase expression in adipose tissue through two mechanisms. The first is indirect and involves inhibition of adipogenesis, while the second occurs more acutely.

KW - Adipogenesis

KW - Adipose tissue

KW - Aromatase

KW - Breast cancer

KW - Endocrine disruption

KW - PPARγ

U2 - 10.1016/j.bcp.2024.116095

DO - 10.1016/j.bcp.2024.116095

M3 - Journal article

C2 - 38423186

AN - SCOPUS:85187337124

VL - 222

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

M1 - 116095

ER -

ID: 385589246