Dehydroepiandrosterone exerts antiglucocorticoid action on human preadipocyte proliferation, differentiation, and glucose uptake
Author(s)
McNelis, Joanne C
Manolopoulos, Konstantinos N
Gathercole, Laura L
Bujalska, Iwona J
Stewart, Paul M
Type
Journal Article
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.
Date Issued
2013-11-01
Date Acceptance
2013-09-09
Citation
American Journal of Physiology - Endocrinology and Metabolism, 2013, 305 (9), pp.E1134-E1144
ISSN
0193-1849
Publisher
American Physiological Society
Start Page
E1134
End Page
E1144
Journal / Book Title
American Journal of Physiology - Endocrinology and Metabolism
Volume
305
Issue
9
Copyright Statement
© 2013 the American Physiological Society. Licensed under Creative Commons Attribution CC-BY 3.0: the American Physiological Society.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/24022868
PII: ajpendo.00314.2012
Subjects
11 beta-hydroxysteroid dehydrogenase type 1
11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1
3T3-L1 ADIPOCYTES
ADIPOCYTE PRECURSOR CELLS
dehydroepiandrosterone
Endocrinology & Metabolism
FAT
GLUCOCORTICOIDS
HEXOSE-6-PHOSPHATE DEHYDROGENASE
human adipogenesis
INDUCED INSULIN-RESISTANCE
INHIBITION
insulin sensitivity
Life Sciences & Biomedicine
METABOLIC SYNDROME
Physiology
Science & Technology
SUBCUTANEOUS ADIPOSE-TISSUE
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2013-11-01