Human Adipose Tissue under in Vitro Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1: Differentiation and Metabolism Changes

Abstract

In humans, oxoreducing 11β-HSD-1 activity appears to be related to body fat distribution in male-type central obesity, but not in female-type peripheral obesity. We postulated that inhibition of 11β-HSD-1 might have clinical therapeutic significance in oxoreducing mostly visceral fat and its metabolic activity. Our current study investigated the consequence at the cellular level of such inhibition. As an inhibitor of 11β-HSD-1 activity, we used the licorice derivative carbenoxolone. Carbenoxolone has an inhibitory effect on the activity of both oxidizing 11β-HSD-2, which converts cortisol to cortisone, and oxoreducing 11β-HSD-1 [1]; yet, preadipocytes and adipocytes only express the latter. Preadipocytes were retrieved from omental and subcutaneous fat from healthy non-obese individuals and differentiated in vitro to mature adipocytes. Activity of 11β-HSD-1 was assayed by measuring conversion of added 500 nM cortisone to cortisol. Expression of 11β-HSD-1 mRNA was determined by real-time PCR, while lipolytic effects were determined by measuring glycerol and triglyceride concentration in the culture medium. Carbenoxolone decreased 11β-HSD-1 activity in a dose-dependent manner with an IC-50 of 5X10^-6 M, but did not affect the expression of 11β-HSD-1 mRNA. Cortisone stimulated subcutaneous, but not omental preadipocytes proliferation, an effect that was not abolished by carbenoxolone. Dexamethasone had a stimulatory effect on the maturation of both omental and subcutaneous preadipocytes. Carbenoxolone per se, either with or without cortisone, had a negative effect on preadipocyte maturation. Inhibiting 11β-HSD-1 activity by carbenoxolone had no impact on leptin secretion. Thus, carbenoxolone has no effect on preadipocyte proliferation, but a dramatic inhibitory effect on preadipocyte differentiation into mature adipocytes. The mechanism is only partly related to its inhibitory effect on 11β-HSD-1 activity. The present observations lend support to the presence of an intracrine loop of a hormone that is both produced from a precursor and active within the preadipocyte and adipocyte.

Key words

11β-HSD-1 - Carbenoxolone - Cortisone

References

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