Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men

Abstract

We examined 5α-dihydrotestosterone (5α-DHT) inactivation and the expression of several steroid-converting enzymes with a focus on aldoketoreductases 1C (AKR1C), especially AKR1C2, in abdominal adipose tissue in men. AKR1C2 is mainly involved in the conversion of the potent androgen 5α-DHT to its inactive forms 5α-androstane-3α/β,17β-diol (3α/β-diol). Subcutaneous (s.c.) and omental (Om) adipose tissue biopsies were obtained from 21 morbidly obese men undergoing biliopancreatic derivation surgery and 11 lean to obese men undergoing general abdominal surgery. AKR1C2 mRNA and 5α-DHT inactivation were detected in both s.c. and Om adipose tissue. After incubation of preadipocytes with 5α-DHT, both 3α-diol and 3β-diol were produced through 3α/β-ketosteroid reductase (3α/β-HSD) activity. In preadipocyte cultures, 3α-reductase activity was significantly predominant over 3β-reductase activity in cells from both the s.c. and Om compartments. Expression levels of AKR1C1, AKR1C3 and of the androgen receptor were significantly higher in s.c. versus Om adipose tissue while mRNA levels of 17β-HSD-2 (hydroxysteroid dehydrogenase type 2) and 3(α→β)-hydroxysteroid epimerase were significantly higher in Om fat. 3α/β-HSD activity was mainly detected in the cytosolic fraction, suggesting that AKR1C may be responsible for this reaction. Experiments with isoform-specific AKR1C inhibitors in preadipocytes showed that AKR1C2 inhibition significantly decreased 3α-HSD and 3β-HSD activities (3α-HSD: 30 ± 24% of control for s.c. and 32 ± 9% of control for Om, 3β-HSD: 44 ± 12% of control for s.c.). When cells were incubated with both AKR1C2 and AKR1C3 inhibitors, no significant additional inhibition was observed. 5α-DHT inactivation was significantly higher in mature adipocytes compared with preadipocyte cultures in s.c. adipose tissue, as expressed per microgram total protein (755 ± 830 versus 245 ± 151 fmol 3α/β-diol per μg protein over 24 h, P < 0.05 n = 10 cultures). 5α-DHT inactivation measured in tissue homogenates was significantly higher in the s.c. depot compared with Om fat (117 ± 39 versus 79 ± 38 fmol 3α/β-diol per μg prot over 24 h, P < 0.0001). On the other hand, Om 3α/β-HSD activity was significantly higher in obese men (body mass index (BMI) ≥ 30 kg/m2) compared with lean and overweight men (84 ± 37 versus 52 ± 30 fmol 3α/β-diol per μg protein over 24 h, P < 0.03). No difference was found in s.c. 3α/β-HSD activity between these groups. Positive correlations were found between s.c. 5α-DHT inactivation rate and circulating levels of the androgen metabolites androsterone-glucuronide (r = 0.41, P < 0.02) and 3α-diol-glucuronide (r = 0.38, P < 0.03) and with the adrenal precursor androstenedione (r = 0.42, P < 0.02). In conclusion, androgen inactivation was detected in abdominal adipose tissue in men, with higher 3α/β-HSD activity in the s.c. versus Om depot. Higher Om 5α-DHT inactivation rates were found in obese compared with lean men. Further studies are required to elucidate whether local androgen inactivation in abdominal adipose tissue is involved in the modulation of adipocyte metabolism and regional fat distribution in men.