Glucocorticoid regulation of P450 aromatase activity in human adipose tissue: Gender and site differences

The distinct gender-specific patterns of fat distribution in men and women (android and gynoid) suggest a role for sex steroids. In keeping with these observations, it has been suggested that estrogens can promote preadipocyte cell proliferation and/or differentiation. The enzyme aromatase P450 is responsible for the conversion of androgen precursor steroids to estrogens and may, therefore, have a role in regulating adipose tissue mass and its distribution. We have investigated the glucocorticoid regulation of aromatase expression in human adipose tissue, specifically to define any site- and gender-specific differences. Abdominal subcutaneous (Sc) and omental (Om) adipose tissue was obtained from male and female patients undergoing elective surgery. After collagenase digestion, preadipocytes were cultured in serum-free medium, for 6-10 d, until confluent with either cortisol (10(-6) M, 10(-7) M) or insulin (500 nM) or a combination of both treatments. Adipocytes were studied in suspension cultures. Aromatase activity was assessed using tritiated [1beta-H-3]-androstenedione as substrate. In Se preadipocytes, basal aromatase activity increased in females from 11.5 +/- 1.4 (mean +/- SEM) to 28.0 +/- 1.8 pmol/mg.h (n = 17, P < 0.05) with 10(-6) M cortisol. By contrast, in males, aromatase activity was inhibited by 10(-6) m cortisol (19.4 +/- 2.4 pmol/mg.h vs. 7.5 +/- 1.3, n = 9, P < 0.01; men vs. women, P < 0.005). These data were endorsed through Western blot analysis using an in-house antihuman aromatase antibody, which recognized a specific 55-kDa species. Aromatase activity was less at Om sites in preadipocytes, increasing in females from 1.1 +/- 0.2 to 3.2 +/- 0.7 pmol/mg.h with 10(-6) m cortisol (P < 0.05) and in males from 2.6 +/- 0.1 pmol/mg.h to 7.8 +/- 0.3 pmol/mg.h after cortisol (men vs. women, P < 0.001). Cortisol-induced aromatase activity in Om adipocytes from postmenopausal females was higher than that in premenopausal females (P < 0.001). Insulin had no independent effect on aromatase expression, but coincubation of preadipocytes with cortisol and insulin eliminated both gender- and site-specific differences. In conclusion, in women, but not men, cortisol increased aromatase activity at Se sites, and this may facilitate predilection for Se adiposity in females. The observed site-, gender-, and menopausal-specific differences in the glucocorticoid regulation of this enzyme may contribute to the gender- and menopausal-specific patterns of fat distribution.