Glucocorticoid Regulation of P450 Aromatase Activity in Human Adipose Tissue: Gender and Site Differences

Abstract

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 genderspecific 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 [1-3 H]-androstenedione as substrate.In Sc preadipocytes, basal aromatase activity increased in females from 11.5 1.4 (mean SEM) to 28.0 1.8 pmol/mgh (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/mgh 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/mgh with 10 6 M cortisol (P < 0.05) and in males from 2.6 0.1 pmol/mgh to 7.8 0.3 pmol/mgh 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 Sc sites, and this may facilitate predilection for Sc 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.