Androgen metabolism in adipose tissue: recent advances

Androgens modulate adipocyte function and affect the size of adipose tissue compartments in humans. Aldo-keto reductase 1C (AKR1C) enzymes, especially AKR1C2 and AKR1C3, through local synthesis and inactivation of androgens, may be involved in the fine regulation of androgen availability in adipose tissue. This review article summarizes recent findings on androgen metabolism in adipose tissue. Primary culture models and whole tissue specimens of human adipose tissue obtained from the abdominal subcutaneous and intra-abdominal (omental) fat compartments were used in our studies. The non-aromatizable androgen dihydrotestosterone (DHT) inhibits adipocyte differentiation in subcutaneous and omental adipocytes in humans. This inhibitory effect is partially reversed by anti-androgens. Activity and mRNA expression of AKR1C1, 2 and 3 were detected in SC and OM adipose tissue, in men and women, with higher levels in the SC depot than the omental depot of both sexes. The abundance of AKR1C enzyme mRNAs was particularly elevated compared to other steroid-converting enzymes. Significant positive associations were observed between AKR1C enzyme mRNA levels or DHT inactivation rates and visceral fat accumulation as well as OM adipocyte size in women and in men, at least in the normal weight to moderately obese range. Mature adipocytes had significantly higher DHT inactivation rates compared to preadipocytes. Accordingly, adipocyte differentiation significantly increased AKR1C enzyme expression and DHT inactivation rates. Treatment of preadipocytes with dexamethasone alone led to significant increases in the formation of 5alpha-androstan-3alpha,17beta-diol. This stimulation was completely abolished by RU486, suggesting that androgen inactivation is stimulated by a glucocorticoid receptor-dependent mechanism. In conclusion, higher AKR1C activity and expression in mature adipocytes may explain the associations between these enzymes and obesity. We speculate that glucocorticoid-induced androgen inactivation could locally decrease the exposure of adipose cells to active androgens and partially remove their inhibitory effect on adipogenesis. We hypothesize that body fat distribution patterns likely emerge from the local adipose tissue balance between active androgens and glucocorticoids in each fat compartment.