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Division of Medical Sciences, Queen Elizabeth Hospital, University of Birmingham (J.W.T., J.M., M.S.C., I.B., M.H., P.M.S.), Birmingham, United Kingdom B15 2TH; Department of Genitourinary Medicine, Selly Oak Hospital (M.S.), Birmingham, United Kingdom B29 6JD; Department of Hepatology, Queen Elizabeth Hospital, University of Birmingham (C.S., A.S.), United Kingdom B15 2TH
Address all correspondence and requests for reprints to: Prof. P. M. Stewart, M.D., F.R.C.P., F.Med.Sci. Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom B15 2TH. E-mail: p.m.stewart{at}bham.ac.uk
Patients with glucocorticoid excess develop central obesity, yet in simple obesity, circulating glucocorticoid levels are normal. We have suggested that the increased activity and expression of the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) generating active cortisol from cortisone within adipose tissue may be crucial in the pathogenesis of obesity. In this study primary cultures of human hepatocytes and adipose stromal cells (ASC) were used as in vitro models to investigate the tissue-specific regulation of 11ßHSD1 expression and activity.
Treatment with tumor necrosis factor-
(TNF) caused a
dose-dependent increase in 11ßHSD1 activity in primary cultures of
both sc [1743.1 ± 1015.4% (TNF, 10 ng/ml);
P < 0.05 vs. control (100%)] and
omental [375.8 ± 57.0% (TNF, 10 ng/ml);
P < 0.01 vs. control (100%)] ASC,
but had no effect on activity in human hepatocytes [90.2 ± 2.8%
(TNF, 10 ng/ml); P = NS vs.
control (100%)]. Insulin-like growth factor I (IGF-I) caused a
dose-dependent inhibition of 11ßHSD1 activity in sc [49.7 ±
15.0% (IGF-I, 100 ng/ml]; P < 0.05
vs. control (100%)] and omental [71.6 ± 7.5
(IGF-I, 100 ng/ml); P < 0.01 vs.
control (100%)] stromal cells, but not in human hepatocytes
[101.8 ± 15.7% (IGF-I, 100 ng/ml); P = NS
vs. control (100%)]. Leptin treatment did not alter
11ßHSD1 activity in human hepatocytes, but increased activity in
omental ASC [135.8 ± 14.1% (leptin, 100 ng/ml);
P = 0.08 vs. control (100%)].
Treatment with interleukin-1ß induced 11ßHSD1 activity and
expression in sc and omental ASC in a time- and dose-dependent manner.
15-Deoxy-
12,14-PGJ2, the putative endogenous ligand of the orphan
nuclear receptor peroxisome proliferator-
, significantly increased
11ßHSD1 activity in omental cells [179.7 ± 29.6% (1
µM); P < 0.05 vs.
control (100%)] and sc [185.3 ± 12.6% (1 µM);
P < 0.01 vs. control (100%)] ASC,
and it is possible that expression of this ligand may ensure continued
cortisol generation to permit adipocyte differentiation. Protease
inhibitors used in the treatment of human immunodeficiency virus
infection are known to cause a lipodystrophic syndrome and central
obesity, but saquinavir, indinavir, and neflinavir caused a
dose-dependent inhibition of 11ßHSD1 activity in primary cultures of
human omental ASC.
11ßHSD1 expression is increased in human adipose tissue by
TNF, interleukin-1ß, leptin, and orphan nuclear receptor
peroxisome proliferator- agonists, but is inhibited by IGF-I. This
autocrine and/or paracrine regulation is tissue specific and explains
recent clinical data and animal studies evaluating cortisol metabolism
in obesity. Tissue-specific 11ßHSD1 regulation offers the potential
for selective enzyme inhibition within adipose tissue as a novel
therapy for visceral obesity.
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