Testosterone inhibits expression of lipogenic genes in visceral fat by an estrogen-dependent mechanism

The influence of the aromatase enzyme on the chronic fat-sparing effects of testosterone requires further elucidation. Our purpose was to determine whether chronic anastrozole (AN, an aromatase inhibitor) treatment alters testosteronemediated lipolytic/lipogenic gene expression in visceral fat. Tenmonth-old Fischer 344 rats (n=6/group) were subjected to sham surgery (SHAM), orchiectomy (ORX), ORX treatment with testosterone enanthate (TEST, 7.0 mg/wk), or ORX TEST AN (0.5 mg/day), with drug treatment beginning 14 days postsurgery. At day 42, ORX animals exhibited nearly undetectable serum testosterone and 29% higher retroperitoneal fat mass than SHAM animals (P 0.001). TEST produced a 380-415% higher serum testosterone than SHAM (P 0.001) and completely prevented ORX-induced visceral fat gain (P 0.001). Retroperitoneal fat was 21% and 16% lower in ORX TEST than SHAM (P 0.001) and ORX TEST AN (P=0.007) animals, while serum estradiol (E2) was 62% (P=0.024) and 87% (P=0.010) higher, respectively. ORX stimulated lipogenicrelated gene expression in visceral fat, demonstrated by 84-154% higher sterol regulatory element-binding protein-1 (SREBP-1, P=0.023), fatty acid synthase (P=0.01), and LPL (P 0.001) mRNA than SHAM animals, effects that were completely prevented in ORX TEST animals (P 0.01 vs. ORX for all). Fatty acid synthase (P=0.061, trend) and LPL (P=0.043) mRNA levels were lower in ORX TEST AN than ORX animals and not different from SHAM animals but remained higher than in ORX TEST animals (P 0.05). In contrast, the ORX-induced elevation in SREBP-1 mRNA was not prevented by TEST AN, with SREBP-1 expression remaining 117-171% higher than in SHAM and ORX TEST animals (P 0.01). Across groups, visceral fat mass and lipogenicrelated gene expression were negatively associated with serum testosterone, but not E2. Aromatase inhibition constrains testosteroneinduced visceral fat loss and the downregulation of key lipogenic genes at the mRNA level, indicating that E2 influences the visceral fat-sparing effects of testosterone.