Year: 2020
Type: dissertation
Abstract: The conversion of androgens to estrogens is catalyzed by the aromatase enzyme, the product of the CYP19A1 gene, in gonads and peripheral tissues. Estrogens produced in the white adipose tissue (WAT) are postulated to play a central role in the development of postmenopausal breast cancer in women and male obesity-related secondary hypogonadism (MOSH). Obesity-related WAT inflammation is considered one of the main driving forces of excessive aromatization in WAT. Regulation of CYP19A1 gene in WAT involves the activation of the glucocorticoiddependent promoter I.4 and the balanced action of local inducers and repressors. This process is complex, and the mechanism behind the link between adiposity, WAT inflammation and excessive aromatization are not well understood. By using the aromatase reporter (hARO-Luc) mouse model and primary adipose stromal cells (ASCs) and adipose tissue samples, two factors, interleukin 10 (IL-10), an anti-inflammatory cytokine, and CC chemokine ligand 2 (CCL2), a proinflammatory chemokine, were found to modulate aromatase gene expression. While IL-10 acts as a suppressor of CYP19A1 via PI.4, CCL2 stimulates this process in ASCs. This was confirmed in vivo in hARO-Luc mouse model, where obesity-related increase in the expression of aromatase reporter in WAT associated with lower IL-10 and/or higher CCL2 levels. Moreover, subcutaneous fat from obese women expresses significantly higher CCL2 and CYP19A1 mRNA levels. As a further proof-of-concept, we showed that attenuation of WAT inflammation by anti-oxidative plant polyphenols in diet is associated with decrease in aromatase reporter expression in hARO-Luc males. In vitro studies confirmed that polyphenols modulate the expression of CYP19A1 in stromal cells. Overall, these results may bring valuable insights into the mechanisms driving aromatase gene expression in WAT in postmenopausal women and men, as well as new approaches for the prevention of breast cancer.
Source: UTUPub (University of Turku)
Author: Gabriela Martínez‐Chacón
Language: English
Subfield: Endocrinology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3003664709