FRI026 PPARγ Antagonists Induce Aromatase Transcription In Human Adipose Tissue Cells

Abstract

Abstract Disclosure: J. Ardenkjær-Skinnerup: None. P.S. Petersen: None. N. Hadrup: None. G. Ravn-Haren: None. B. Emanuelli: None. U.B. Vogel: None. K.A. Brown: None. Peroxisome proliferator-activated receptor gamma (PPARγ) activation in adipose stromal cells (ASCs; adipocyte precursors) is associated with decreased expression of the estrogen biosynthetic enzyme, aromatase, encoded by the CYP19A1 gene. A number of chemicals and endocrine disruptors can affect PPARγ function. For example, ethanol-mediated inhibition of PPARγ activity is associated with increased risk of breast cancer,1 and a potential mechanism has been suggested to involve upregulation of aromatase. It is therefore hypothesized that inhibitors of PPARγ will induce aromatase expression and may act as breast carcinogens. This study aimed to explore the effect of PPARγ antagonists on the expression of aromatase in cells from human adipose tissue. Human adipose tissue was obtained from abdominoplasty or reduction mammoplasty surgeries. Explants, adipocytes and ASCs were collected for culture and/or gene expression analysis. Primary ASCs and the hTERT A41 hWAT ASC line were differentiated in the presence of PPARγ antagonists followed by gene expression analysis or lipid staining. Adipose tissue explants and A41 cells were treated for 24 or 48 h with PPARγ agonist or antagonist, and gene expression analysis was performed. Finally, PPARγ was overexpressed in A41 cells and/or treated with a PPARγ agonist to study the effect of PPARγ protein level and activation on aromatase expression. Aromatase expression was higher in human ASCs than in mature adipocytes. Exposure of ASCs to PPARγ antagonists during differentiation inhibited lipid accumulation and resulted in higher expression of aromatase. PPARγ overexpression and agonist treatment repressed aromatase expression in A41 cells, while antagonist treatment in differentiated A41 cells resulted in increased aromatase expression. A similar tendency was observed in adipose tissue explants. In conclusion, the results suggest that PPARγ regulates aromatase through two separate mechanisms. Exposure of human ASCs to PPARγ antagonists indirectly upregulates aromatase expression by inhibition of adipogenesis. In addition, PPARγ regulates aromatase in differentiated ASCs via a more acute mechanism, not related to adipocyte differentiation. 1. Petersen RK, Larsen SB, Jensen DM, et al. PPARgamma-PGC-1alpha activity is determinant of alcohol related breast cancer. Cancer Lett. 2012;315(1):59-68. Presentation: Friday, June 16, 2023