A novel selective 11b-hydroxysteroid dehydrogenase type 1 inhibitor prevents human adipogenesis

11b-HSD1 is essential for human adipogenesis . I J BUJALSKA and others 305

Days of treatment

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° 0∙10

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□ Non-Clifferentiated

■ DM 2(E)

□ DM 2(E+PF-877423)

16          20          22

Figure 7 (A) Effect of chronic exposure to the selective 11 b-HSD1 inhibitor PF-877423 on subcutaneous s-v cells. 11
b-HSD1 enzyme inhibition by 300 nM PF-877423 measured as the production of cortisol (day 6: 154G8 vs 5387G182;
day 9: 128G1 vs 5489G230; day 14: 174G18 vs 4041G106; day 20: 409G27 vs 10443G78; day 22: 330G7 vs
11218G193 pg/ml per 24 h, meanGS.D., P!0.001, nZ3, EK or ECPF-877423-treated respectively). (B) Inhibition of
lipid accumulation by 300 nM PF-877423 in subcutaneous stromal-vascular cells (day 16: 0.25G0.03 vs 0.20G0.01;
day 20: 0.3G0.02 vs 0.20G0.01; day 22: 0.27G0.01 vs 0.19G0.01; OD (500/660 nm), nZ3, EK or
ECPF-877423-treated respectively), P values: **P!0.01, ***P!0.001.

glucose tolerance through reduced gluconeogenesis and hepatic
glucose output (Kotelevtsev et al. 1997, Morton et al. 2001),
while targeted overexpression of 11b-HSD1 in adipose tissue
recapitulates features of the MS including central adiposity
(Masuzaki et al. 2001). In the liver of db/db mice (a model of
type 2 diabetes), GR and 11b-HSD1 mRNA expression
positively correlated with blood insulin and glucose (Liu et al.
2005). Inhibition of GR and 11b-HSD1 expression either with
GR antagonist (RU486; Liu et al. 2005) orby chronic activation
of liver X receptor (Liu et al. 2006) attenuated the phenotype of
type 2 diabetes in mice.

In humans, the situation is less clear with regard to a role for
11b-HSD1 in the pathogenesis of MS. Some authors have
argued for a primary overexpression of 11b-HSD1 in affected
patients akin to that observed in some animal models
(Paulmyer-Lacroix et al. 2002, Rask et al. 2002). However,
while the expression of 11b-HSD1 might be increased, at least
in subcutaneous adipose tissue in obese patients with MS and
type 2 diabetes (Tomlinson et al. 2002, Alberti et al. 2007), no
such increase was observed in omental adipose tissue.
Furthermore, based on urinary cortisol/cortisone metabolite
ratios and plasma cortisol generation curves following oral
cortisone acetate that primarily reflects hepatic 11b-HSD1
expression, a reduction, not an increase, in 11b-HSD1
expression was observed at least in subjects with simple obesity
(Stewart et al. 1999, Tomlinson et al. 2004). We have argued that
obesity is not primarily a state of 11b-HSD1 overexpression, but
that the fall in hepatic 11b-HSD1 activity with increased visceral
adiposity might serve as a protective mechanism to offset hepatic
glucose output and further adiposity (Valsamakis et al. 2004).
Failure of such a switch off in 11b-HSD1 expression might be a
factor that determines the onset and persistence of hypergly-
caemia in obese patients with type 2 diabetes mellitus
(Valsamakis et al. 2004). Further studies are indicated to define
the exact role of 11b-HSD1 in the pathophysiology of human
MS. Irrespective of the outcome of these studies, selective
inhibitors such as PF-877423 offer a real advance in the
prevention and treatment of diabetes in subjects with obesity
with the potential added benefit of inhibiting adipocyte
differentiation. A reduction in adipogenesis specifically within
omental depots is likely to further improve the metabolic
phenotype of these patients. Clinical studies characterising a
novel, potent (K_i 0.2 nM) and fully selective 11b-HSD1
inhibitor preventing lipogenesis in vitro will further our
understanding of the role of local glucocorticoid metabolism
in human adipose tissue.

Acknowledgements

The work was supported by a Wellcome Trust Programme
Grant (Ref No 066357) and MRC Grant (G0502165). The
authors thank Jeff Zhu for providing the human 11b-HSD1
recombinant protein.

Disclosure

I J B, L L G, J W T and C D declare no conflict of interest. J E,
A N F and P A R are employed by Pfizer. P M S is on the
advisory board for Pfizer Global R&D.

References

Alberti L, Girola A, Gilardini L, Conti A, Cattaldo S, Micheletto G & Invitti
C 2007 Type 2 diabetes and metabolic syndrome are associated with
increased expression of 11b-hydroxysteroid dehydrogenase 1 in obese
subjects. International Journal of Obesity 31 1826—1831.

Journal of Endocrinology (2008) 197, 297-307

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