PPARγ antagonists induce aromatase transcription in adipose tissue cultures
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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.
Originalsprog | Engelsk |
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Artikelnummer | 116095 |
Tidsskrift | Biochemical Pharmacology |
Vol/bind | 222 |
Antal sider | 13 |
ISSN | 0006-2952 |
DOI | |
Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
We thank the laboratory technicians at the National Food Institute, Maud Bering Andersen and Dorte Lykkegaard Korsbech, for their work and technical assistance, and Jason A. Spector, Department of Surgery at Weill Cornell Medicine, for facilitating access to reduction mammoplasty tissue. We also thank Karsten Kristiansen, University of Copenhagen, Denmark for kindly providing the plasmids pcDNA3.1 and pcDNA3.1 PPARG2. Studies were conducted with the support provided by the Center for Translational Pathology at Weill Cornell Medicine. This work was supported by FFIKA, Focused Research Effort on Chemicals in the Working Environment, from the Danish Government and by the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent research center at the University of Copenhagen, Denmark, partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900). KAB was supported by the National Cancer Institute of the National Institutes of Health, United States, grant 1R01CA215797, the Anne Moore Breast Cancer Research Fund, and the Emilie Lippmann and Janice Jacobs McCarthy Research Scholar Award in Breast Cancer. JAS was supported by Idella Foundation, William Demant Foundation, and Christian and Ottilia Brorson Travel Grant. DS was supported by Studienstiftung des Deutschen Volkes (German Academic Scholarship Foundation). BBK was supported by the Novo Nordisk Foundation Challenge Center REPIN (NNF18OC0033926). NMR data were recorded at cOpenNMR, an infrastructure supported by the Novo Nordisk Foundation (NNF18OC0032996).
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© 2024 The Authors
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