A Switch in Dehydrogenase to Reductase Activity of 11 -Hydroxysteroid Dehydrogenase Type 1 upon Differentiation of Human Omental Adipose Stromal Cells

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Abstract
As exemplified in patients with Cushing's syndrome, glu- cocorticoids play an important role in regulating adipose tis- sue distribution and function, but circulating cortisol con- centrations are normal in most patients with obesity. However, human omental adipose stromal cells (ASCs) can generate glucocorticoid locally through the expression of the enzyme 11-hydroxysteroid dehydrogenase (11-HSD) type 1 (11-HSD1), which, in intact cells, has been considered to be an oxoreductase, converting inactive cortisone (E) to cortisol (F). Locally produced F can induce ASC differentiation, but the relationship between 11-HSD1 expression and adipocyte differentiation is unknown. Primary cultures of paired omen- tal (om) and sc ASC and adipocytes were prepared from 17 patients undergoing elective abdominal surgery and cultured for up to 14 d. Expression and activity of 11-HSD isozymes were analyzed together with early (lipoprotein lipase) and terminal (glycerol 3 phosphate dehydrogenase) markers of adipocyte differentiation. O nd1o fculture, 11-HSD1 activity in intact om ASCs exceeded oxoreductase activity in every patient (78.9 24.9 vs. 15.8 3.7 (mean SE) pmol/mg per hour, P < 0.001), and in sc ASCs, relative activities were similar (40.6 12.2 vs. 36.9 8.8). Conversely, in freshly isolated om adipocytes, reductase activity exceeded dehydrogenase ac- tivity (23.6 1.5 vs. 6.2 0.8 pmol/mg per hour, P < 0.01). Following 14 d of culture in serum-free conditions with addi- tion of 10 nM insulin (Ctr) or insulin with 100 nM F( F), li- poprotein lipase/18S RNA levels increased in both the Ctr- and F-treated ASCs, but glycerol 3 phosphate dehydrogenase in- creased only in the F cultures. In both cases, however, 11- HSD1 oxoreductase activity exceeded dehydrogenase activity (Ctr: 53.3 9.0 vs. 32.4 10.5, P < 0.05; F: 65.6 15.6 vs. 37.1 11.5 pmol/mg per hour, P < 0.05), despite no significant changes in 11-HSD1 mRNA levels. In sc ASCs, dehydrogenase activity was similar to reductase activity in both Ctr- and F-treated cells. Type 2 11-HSD expression was undetect- able in each case. These data show that in intact, undifferen- tiated om ASCs, 11-HSD1 acts primarily as a dehydrogenase, but in mature adipocytes oxoreductase activity predomi- nates. Because glucocorticoids inhibit cell proliferation, we postulate that 11-HSD1 activity in uncommitted ASCs may facilitate proliferation rather than differentiation. Once early differentiation is initiated, a "switch" to 11-HSD1 oxoreduc- tase activity generates F, thus promoting adipogenesis. Site- specific regulation of the set-point of 11-HSD1 activity may be an important mechanism underpinning visceral obesity. (J Clin Endocrinol Metab 87: 1205-1210, 2002)

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