PMID- 11889189
OWN - NLM
STAT- MEDLINE
DCOM- 20020408
LR  - 20171116
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 87
IP  - 3
DP  - 2002 Mar
TI  - A switch in dehydrogenase to reductase activity of 11 beta-hydroxysteroid 
      dehydrogenase type 1 upon differentiation of human omental adipose stromal cells.
PG  - 1205-10
AB  - 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 11 beta-hydroxysteroid dehydrogenase 
      (11 beta-HSD) type 1 (11 beta-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 
      beta-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 11 beta-HSD isozymes were analyzed together with early (lipoprotein 
      lipase) and terminal (glycerol 3 phosphate dehydrogenase) markers of adipocyte 
      differentiation. On d 1 of culture, 11 beta-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, 11 beta-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 
      beta-HSD1 mRNA levels. In sc ASCs, dehydrogenase activity was similar to 
      reductase activity in both Ctr- and +F-treated cells. Type 2 11 beta-HSD 
      expression was undetectable in each case. These data show that in intact, 
      undifferentiated om ASCs, 11 beta-HSD1 acts primarily as a dehydrogenase, but in 
      mature adipocytes oxoreductase activity predominates. Because glucocorticoids 
      inhibit cell proliferation, we postulate that 11 beta-HSD1 activity in 
      uncommitted ASCs may facilitate proliferation rather than differentiation. Once 
      early differentiation is initiated, a "switch" to 11 beta-HSD1 oxoreductase 
      activity generates F, thus promoting adipogenesis. Site-specific regulation of 
      the set-point of 11 beta-HSD1 activity may be an important mechanism underpinning 
      visceral obesity.
FAU - Bujalska, Iwona J
AU  - Bujalska IJ
AD  - Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, 
      Birmingham B15 2TH, United Kingdom.
FAU - Walker, Elizabeth A
AU  - Walker EA
FAU - Hewison, Martin
AU  - Hewison M
FAU - Stewart, Paul M
AU  - Stewart PM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - EC 1.- (Oxidoreductases)
RN  - EC 1.1.- (Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.1.146 (11-beta-Hydroxysteroid Dehydrogenase Type 2)
RN  - EC 1.1.1.146 (HSD11B2 protein, human)
SB  - IM
MH  - 11-beta-Hydroxysteroid Dehydrogenase Type 2
MH  - Adipocytes/*cytology/physiology
MH  - Cell Differentiation/physiology
MH  - Cells, Cultured
MH  - Cellular Senescence/physiology
MH  - Female
MH  - Humans
MH  - Hydroxysteroid Dehydrogenases/*metabolism
MH  - Male
MH  - Middle Aged
MH  - Omentum/*cytology/*enzymology
MH  - Oxidoreductases/metabolism
MH  - Stromal Cells/*cytology
MH  - Time Factors
EDAT- 2002/03/13 10:00
MHDA- 2002/04/09 10:01
CRDT- 2002/03/13 10:00
PHST- 2002/03/13 10:00 [pubmed]
PHST- 2002/04/09 10:01 [medline]
PHST- 2002/03/13 10:00 [entrez]
AID - 10.1210/jcem.87.3.8301 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2002 Mar;87(3):1205-10. doi: 10.1210/jcem.87.3.8301.