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

Testosterone is closely associated with lipid metabolism and known to affect body fat composition and muscle mass in males. However, the mechanisms by which testosterone acts on lipid metabolism are not yet fully understood, especially in teleosts. In this study, -/- zebrafish ( ) exhibited excessive visceral adipose tissue (VAT), lipid content, and up-regulated expression and activity of hepatic lipogenesis (DNL) enzymes. The assay for transposase accessible chromatin with sequencing (ATAC-seq) results demonstrated that chromatin accessibility of DNL genes was increased in -/- fish compared to +/+ male fish, including stearoyl-CoA desaturase ( ) and fatty acid synthase ( ). Androgen response element (ARE) motifs in the androgen signaling pathway were significantly enriched in +/+ male fish but not in -/- fish. Both androgen receptor ( )-/- and wild-type (WT) zebrafish administered with Ar antagonist flutamide displayed excessive visceral adipose tissue, lipid content, and up-regulated expression and activity of hepatic lipogenesis enzymes. The Ar agonist BMS-564929 reduced the content of VAT and lipid content, and down-regulated acetyl-CoA carboxylase a ( ), , and expression. Mechanistically, the rescue effect of testosterone on -/- fish in terms of phenotypes was abolished when was additionally depleted. Collectively, these findings reveal that testosterone inhibits lipid deposition by down-regulating DNL genes via Ar in zebrafish, thus expanding our understanding of the relationship between testosterone and lipid metabolism in teleosts.