Abstract and Introduction
Abstract
Context: 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) may be involved in the local modulation of estradiol (E2) availability in adipose tissues. Objective: To assess the conversion of E2 into estrone (E1) as well as the expression of 17β-HSD2 and its localization in omental (OM) and subcutaneous (SC) adipose tissues obtained from women. Methods: Rates of 14C-E1 formation from 14C-E2 were measured in OM and SC adipose tissue homogenates from 29 women. Specific 17β-HSD2 inhibitor EM-919 was tested in OM and SC adipose tissue homogenates (n = 6). 17β-HSD2 mRNA expression was measured in whole OM and SC adipose tissues (n = 14). Cellular localization of the enzyme was examined using immunohistochemistry. Anthropometric measurements were obtained and body composition as well as body fat distribution were measured. Results: Significant 14C-E1 formation from 14C-E2 in OM and SC tissue homogenates was detected. The rate of 14C-E1 formation was significantly higher in OM than SC adipose tissue (p < .0001). The conversion of 14C-E2 to 14C-E1 was significantly inhibited by EM-919 in OM (p < .05) and SC (p < .05) adipose tissues. Significantly higher expression of 17β-HSD2 mRNA in OM versus SC fat was found (p = .03). 17β-HSD2 was localized in the vasculature of OM and SC tissues. Significant negative associations were detected between OM 17β-HSD2 activity and body mass index, WC, lean body mass as well as SC adipose tissue areas. Conclusion: 17β-HSD2 converts E2 to E1 in OM and SC adipose tissues of women. The activity of this enzyme decreases with increasing adiposity.
Introduction
Ovaries are the main source of oestrogens in premenopausal women. However, oestrogens are also produced locally in peripheral tissues of women and men, especially adipose tissues, through aromatization of androgens.[1] Although significant central effects of oestrogens have been reported on energy balance,[2,3] other studies have described peripheral oestrogen action on adipose tissue metabolism.[4] This is supported by the presence of both oestrogen receptors (ER) α and β.[5,6] Many aspects of oestrogenic action remain to be clarified, but most investigators agree that estradiol (E2) likely plays an important role in the regulation of adipose tissue function and metabolism (reviewed in).[7]
Steroid-converting enzymes responsible for E2 synthesis in adipose tissue contribute not only to local hormone availability, but also to oestrogen dynamics at the whole-body level (reviewed in).[7] For example, 17β-hydroxysteroid dehydrogenases (17β-HSDs) play a role in the modulation of active steroid hormone availability including oestrogens and androgens.[8,9] These enzymes are widely distributed in human tissues, not only in steroidogenic tissues such as the testis, ovary and placenta, but also in peripheral sites including adipose tissue.[10,11]
Among 17β-HSD isoenzymes, 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) is a 1.4- kilobase cDNA encoding a 387 amino acid protein with a MW of 42.7 kDa.[8] It catalyzes the conversion of active 17β-hydroxysteroids into less active 17-ketosteroids with NAD+ as cofactor, which decreases tissue levels of active oestrogens and androgens.[12] More specifically, it is responsible for the conversion of testosterone to androstenedione (4-dione), of E2 to estrone (E1) and of 20α-dihydroxyprogesterone to progesterone.[8] In transfected HEK293 cells, 17β-HSD2 also exhibits 3β-HSD activity.[13] It is expressed in the liver, placenta, endometrium and small intestine.[8] In another publication,[10] we have shown that 17β-HSD2 expression and activity were higher in OM than in SC adipose tissue of men. We also localized the enzyme in the adipose tissue vasculature. The enzyme activity was positively correlated with markers of obesity.
To the best of our knowledge, no study investigated 17β-HSD2 activity and localization in abdominal adipose tissues of women. Our objective was to detect the conversion of E2 into E1 as well as the expression and localization of 17β-HSD2 in omental (OM) and subcutaneous (SC) adipose tissue obtained from women. We hypothesized: (1) that the conversion of E2 to E1 is present in OM and SC adipose tissues in women; (2) that 17β-HSD type 2 is responsible for this conversion; and (3) that conversion rate is associated with anthropometric measurements as well as adiposity markers.
Clin Endocrinol. 2023;98(2):229-237. © 2023 Blackwell Publishing