Abstract
Glucocorticoids increase adipocyte proliferation and differentiation, a process underpinned by the local reactivation of inactive cortisone to active cortisol within adipocytes catalyzed by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The adrenal sex steroid precursor dehydroepiandrosterone (DHEA) has been shown to inhibit 11β-HSD1 in murine adipocytes; however, rodent adrenals do not produce DHEA physiologically. Here, we aimed to determine the effects and underlying mechanisms of the potential antiglucocorticoid action of DHEA and its sulfate ester DHEAS in human preadipocytes. Utilizing a human subcutaneous preadipocyte cell line, Chub-S7, we examined the metabolism and effects of DHEA in human adipocytes, including adipocyte proliferation, differentiation, 11β-HSD1 expression, and activity and glucose uptake. DHEA, but not DHEAS, significantly inhibited preadipocyte proliferation via cell cycle arrest in the G1 phase independent of sex steroid and glucocorticoid receptor activation. 11β-HSD1 oxoreductase activity in differentiated adipocytes was inhibited by DHEA. DHEA coincubated with cortisone significantly inhibited preadipocyte differentiation, which was assessed by the expression of markers of early (LPL) and terminal (G3PDH) adipocyte differentiation. Coincubation with cortisol, negating the requirement for 11β-HSD1 oxoreductase activity, diminished the inhibitory effect of DHEA. Further consistent with glucocorticoid-opposing effects of DHEA, insulin-independent glucose uptake was significantly enhanced by DHEA treatment. DHEA increases basal glucose uptake and inhibits human preadipocyte proliferation and differentiation, thereby exerting an antiglucocorticoid action. DHEA inhibition of the amplification of glucocorticoid action mediated by 11β-HSD1 contributes to the inhibitory effect of DHEA on human preadipocyte differentiation.
Highlights
GLUCOCORTICOID EXCESS characteristically causes central obesity and insulin resistance
It was shown that DHEA inhibits proliferation in PAZ6 preadipocytes, a cell line derived from human brown adipose tissue, and adipogenesis in omental but not subcutaneous preadipocytes [39], highlighting possible depot-specific effects of DHEA
The white adipose tissue marker fatty acid-binding protein 4 (FABP4) was undetectable in undifferentiated Chub-S7 cells but was expressed at levels comparable with human mature adipocytes (2.4 Ϯ 0.9 vs. 2.3 Ϯ 0.0001 arbitrary units (AU)) following differentiation (Fig. 1B)
Summary
GLUCOCORTICOID EXCESS characteristically causes central obesity and insulin resistance. In addition to its indirect role as a steroid precursor, DHEA can elicit direct effects in immune and vascular endothelial cells [35], a specific receptor has as yet not been characterized. These studies have highlighted distinct roles for DHEA and DHEAS [16, 38]. The expression and activity of 11-HSD1 is inhibited by DHEA in murine adipocytes [2, 43] and rat liver [22], providing a potential mechanism by which the effects of DHEA oppose those of glucocorticoids. E1135 was twofold; first, provide a comprehensive analysis of DHEA metabolism in human adipocytes and the effects of DHEA and DHEAS on human adipogenesis, and second, examine the effect of DHEA on 11-HSD1 in human adipocytes and resulting glucocorticoid reactivation based on our hypothesis that DHEA inhibits adipogenesis via 11-HSD1
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