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Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom
Address all correspondence and requests for reprints to: Paul M Stewart, M.D., F.R.C.P., F.Med.Sci., Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom. E-mail: . p.m.stewart{at}bham.ac.uk
Abstract
As exemplified in patients with Cushing’s syndrome, glucocorticoids play an important role in regulating adipose tissue distribution and function, but circulating cortisol concentrations are normal in most patients with obesity. However, human omental adipose stromal cells (ASCs) can generate glucocorticoid locally through the expression of the enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD) type 1 (11ß-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 11ß-HSD1 expression and adipocyte differentiation is unknown. Primary cultures of paired omental (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 11ß-HSD isozymes were analyzed together with early (lipoprotein lipase) and terminal (glycerol 3 phosphate dehydrogenase) markers of adipocyte differentiation. On d 1 of culture, 11ß-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 activity (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 addition of 10 nM insulin (Ctr) or insulin with 100 nM F (+F), lipoprotein lipase/18S RNA levels increased in both the Ctr- and +F-treated ASCs, but glycerol 3 phosphate dehydrogenase increased only in the +F cultures. In both cases, however, 11ß-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 11ß-HSD1 mRNA levels. In sc ASCs, dehydrogenase activity was similar to reductase activity in both Ctr- and +F-treated cells. Type 2 11ß-HSD expression was undetectable in each case. These data show that in intact, undifferentiated om ASCs, 11ß-HSD1 acts primarily as a dehydrogenase, but in mature adipocytes oxoreductase activity predominates. Because glucocorticoids inhibit cell proliferation, we postulate that 11ß-HSD1 activity in uncommitted ASCs may facilitate proliferation rather than differentiation. Once early differentiation is initiated, a "switch" to 11ß-HSD1 oxoreductase activity generates F, thus promoting adipogenesis. Site-specific regulation of the set-point of 11ß-HSD1 activity may be an important mechanism underpinning visceral obesity.
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