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.