11Beta-hydroxysteroid dehydrogenase type 1 in differentiating omental human preadipocytes: from de-activation to generation of cortisol.
In humans, glucocorticoids are important regulators of adipose tissue distribution and function but circulating cortisol concentrations are normal in most patients with obesity. However, intracellular glucocorticoid levels can be modified by a microsomal enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) expressed mainly in the liver and adipose tissue. Locally generated cortisol within human adipose tissue can induce preadipocyte differentiation, but the relationship between 11beta-HSD1 expression and adipogenesis is unknown. Our present study has shown that in intact, undifferentiated omental (OM) but not subcutaneous (SC) preadipocytes, 11beta-HSD1 acts primarily as a dehydrogenase inactivating cortisol to cortisone. When preadipocytes become "committed" to adipocyte differentiation, oxo-reductase activity predominates generating cortisol. Since glucocorticoids are not only essential for OM preadipocyte differentiation but also inhibit cell proliferation, we postulate that 11beta-HSD1 dehydrogenase activity in "uncommitted" OM preadipocytes may provide an autocrine mechanism to protect preadipocytes from differentiation, in turn facilitating their proliferation. Once early differentiation is initiated, a "switch" to 11beta-HSD1 oxo-reductase activity generates cortisol, thus promoting adipogenesis. The differences in set-point of 11beta-HSD1 activity between OM and SC human adipose tissue may be an important factor in the pathogenesis of visceral obesity.
Bujalska
Iwona J
IJ
Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, UK.
Walker
Elizabeth A
EA
Tomlinson
Jeremy W
JW
Hewison
Martin
M
Stewart
Paul M
PM
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D017667:Adipocytes / Q000166:cytology / Q000201:enzymology*; D002454:Cell Differentiation / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis*; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D009852:Omentum / Q000166:cytology* / Q000201:enzymology*; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology*
D006913:Hydroxysteroid Dehydrogenases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D006854:Hydrocortisone