Glucocorticoid-induced androgen inactivation by aldo-keto reductase 1C2 promotes adipogenesis in human preadipocytes.

Adipogenesis and lipid storage in human adipose tissue are inhibited by androgens such as DHT. Inactivation of DHT to 3α-diol is stimulated by glucocorticoids in human preadipocytes. We sought to characterize glucocorticoid-induced androgen inactivation in human preadipocytes and to establish its role in the antiadipogenic action of DHT. Subcutaneous and omental primary preadipocyte cultures were established from fat samples obtained in subjects undergoing abdominal surgeries. Inactivation of DHT to 3α/β-diol for 24 h was measured in dexamethasone- or vehicle-treated cells. Specific downregulation of aldo-keto reductase 1C (AKR1C) enzymes in human preadipocytes was achieved using RNA interference. In whole adipose tissue sample, cortisol production was positively correlated with androgen inactivation in both subcutaneous and omental adipose tissue (P < 0.05). Maximal dexamethasone (1 μM) stimulation of DHT inactivation was higher in omental compared with subcutaneous fat from men as well as subcutaneous and omental fat from women (P < 0.05). A significant positive correlation was observed between BMI and maximal dexamethasone-induced DHT inactivation rates in subcutaneous and omental adipose tissue of men and women (r = 0.24, n = 26, P < 0.01). siRNA-induced downregulation of AKR1C2, but not AKR1C1 or AKR1C3, significantly reduced basal and glucocorticoid-induced androgen inactivation rates (P < 0.05). The inhibitory action of DHT on preadipocyte differentiation was potentiated following AKR1C2 but not AKR1C1 or AKR1C3 downregulation. Specifically, lipid accumulation, G3PDH activity, and FABP4 mRNA expression in differentiated preadipocytes exposed to DHT were reduced further upon AKR1C2 siRNA transfection. We conclude that glucocorticoid-induced androgen inactivation is mediated by AKR1C2 and is particularly effective in omental preadipocytes of obese men. The interplay between glucocorticoids and AKR1C2-dependent androgen inactivation may locally modulate adipogenesis and lipid accumulation in a depot-specific manner.

[1]  A. Veilleux,et al.  Expression of genes related to glucocorticoid action in human subcutaneous and omental adipose tissue , 2010, The Journal of Steroid Biochemistry and Molecular Biology.

[2]  A. Veilleux,et al.  Effects of androgens on adipocyte differentiation and adipose tissue explant metabolism in men and women , 2010, Clinical endocrinology.

[3]  A. Veilleux,et al.  Omental adipose tissue type 1 11 beta-hydroxysteroid dehydrogenase oxoreductase activity, body fat distribution, and metabolic alterations in women. , 2009, The Journal of clinical endocrinology and metabolism.

[4]  A. Veilleux,et al.  Androgen metabolism in adipose tissue: Recent advances , 2009, Molecular and Cellular Endocrinology.

[5]  A. Tchernof,et al.  Pathways of adipose tissue androgen metabolism in women: depot differences and modulation by adipogenesis. , 2009, American journal of physiology. Endocrinology and metabolism.

[6]  F. Faucher,et al.  Progesterone metabolism in adipose cells , 2009, Molecular and Cellular Endocrinology.

[7]  N. LeBrasseur,et al.  Effects of dihydrotestosterone on differentiation and proliferation of human mesenchymal stem cells and preadipocytes , 2008, Molecular and Cellular Endocrinology.

[8]  M. Jensen,et al.  Omental 11β‐hydroxysteroid Dehydrogenase 1 Correlates with Fat Cell Size Independently of Obesity , 2007, Obesity.

[9]  T. Olsson,et al.  Intra‐adipose sex steroid metabolism and body fat distribution in idiopathic human obesity , 2007, Clinical endocrinology.

[10]  A. Tchernof,et al.  Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men. , 2006, The Journal of endocrinology.

[11]  M. Quinkler,et al.  Depot-specific prostaglandin synthesis in human adipose tissue: a novel possible mechanism of adipogenesis. , 2006, Gene.

[12]  S. Bhasin,et al.  Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with beta-catenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors. , 2006, Endocrinology.

[13]  C. Bouchard,et al.  Contribution of age and declining androgen levels to features of the metabolic syndrome in men. , 2005, Metabolism: clinical and experimental.

[14]  P. Dupont,et al.  Expression and activity of steroid aldoketoreductases 1C in omental adipose tissue are positive correlates of adiposity in women. , 2005, American journal of physiology. Endocrinology and metabolism.

[15]  P. Dupont,et al.  Expression and activity of 20alpha-hydroxysteroid dehydrogenase (AKR1C1) in abdominal subcutaneous and omental adipose tissue in women. , 2005, The Journal of clinical endocrinology and metabolism.

[16]  H. Hauner,et al.  Comparison of proliferation and differentiation capacity of human adipocyte precursor cells from the omental and subcutaneous adipose tissue depot of obese subjects. , 2004, Metabolism: clinical and experimental.

[17]  M. Quinkler,et al.  Androgen generation in adipose tissue in women with simple obesity--a site-specific role for 17beta-hydroxysteroid dehydrogenase type 5. , 2004, The Journal of endocrinology.

[18]  P. Dupont,et al.  Local androgen inactivation in abdominal visceral adipose tissue. , 2003, The Journal of clinical endocrinology and metabolism.

[19]  H. Hauner,et al.  Comparison of proliferation and differentiation capacity of human adipocyte precursor cells from the omental and subcutaneous adipose tissue depot of obese subjects. , 2003, Metabolism: clinical and experimental.

[20]  R. Kingston,et al.  Calcium Phosphate Transfection , 1997, Current protocols in neuroscience.

[21]  V. Luu‐The,et al.  Characterization of a human 20alpha-hydroxysteroid dehydrogenase. , 2000, Journal of molecular endocrinology.

[22]  E. Poehlman,et al.  Sex hormone-binding globulin levels in middle-aged premenopausal women. Associations with visceral obesity and metabolic profile. , 1999, Diabetes care.

[23]  S. Yeh,et al.  Identification of ARA70 as a Ligand-enhanced Coactivator for the Peroxisome Proliferator-activated Receptor γ* , 1999, The Journal of Biological Chemistry.

[24]  M. Hewison,et al.  Differentiation of adipose stromal cells: the roles of glucocorticoids and 11beta-hydroxysteroid dehydrogenase. , 1999, Endocrinology.

[25]  T. Penning,et al.  Dexamethasone regulation of the rat 3alpha-hydroxysteroid/dihydrodiol dehydrogenase gene. , 1998, Molecular pharmacology.

[26]  P. Björntorp,et al.  Blockade of the glucocorticoid receptor with RU 486: effects in vitro and in vivo on human adipose tissue lipoprotein lipase activity. , 1995, Obesity research.

[27]  C. Remacle,et al.  Glucocorticoids induce a drastic inhibition of proliferation and stimulate differentiation of adult rat fat cell precursors. , 1991, Experimental cell research.

[28]  M. Wabitsch,et al.  Promoting effect of glucocorticoids on the differentiation of human adipocyte precursor cells cultured in a chemically defined medium. , 1989, The Journal of clinical investigation.

[29]  M. Rodbell.  METABOLISM OF ISOLATED FAT CELLS. I. EFFECTS OF HORMONES ON GLUCOSE METABOLISM AND LIPOLYSIS. , 1964, The Journal of biological chemistry.