Androgen signaling inhibits de novo lipogenesis to alleviate lipid deposition in zebrafish

Lipid metabolism is closely associated with testosterone, which is known to affect body fat composition and muscle mass in males. However, the mechanism by which testosterone acts on lipid metabolism is not fully clear yet, especially in teleosts. In this study, we firstly observed that cyp17a1-/- zebrafish (Danio rerio) exhibited excessive visceral adipose tissue (VAT), lipid content and up-regulated expression and activity of hepatic de novo lipogenesis (DNL) enzymes. The result of Assay for Transposase Accessible Chromatin with sequencing (ATAC-seq) demonstrated that chromatin accessibility of DNL genes were increased in cyp17a1-/- fish compared to cyp17a1+/+ male fish, including stearoyl-CoA desaturase (scd) and fatty acid synthase (fasn). Androgen receptor element (ARE) motif in the androgen signaling pathway was significantly enriched in cyp17a1+/+ male fish but not in cyp17a1-/- fish. Both androgen receptor (ar)-/- zebrafish and wild-type (WT) zebrafish administrated with Ar antagonist Flutamide exhibited excessive visceral adipose tissue, lipid content and up-regulated expression and activity of hepatic de novo lipogenesis (DNL) enzymes. The Ar agonist, BMS-564929, diminished the content of VAT and lipid content, and down-regulated acetyl-CoA carboxylase a (acaca), fasn and scd expression. Mechanistically, the rescuing effect of testosterone on cyp17a1-/- fish in terms of the the phenotypes mentioned above was abolished when ar was additionally depleted. Collectively, our findings revealed that testosterone inhibits lipid deposition by down-regulating DNL genes via Ar in zebrafish, which expand the understanding of the relationship between testosterone and lipid metabolism in teleosts.