College of Fisheries, Huazhong Agriculture University
State key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences
Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes Chinese Sturgeon Research Institute, China Three Gorges Corporation
State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences
This work was supported by the National Key Research and Development Program, China (2022YFF1000300 to ZY and 2022YFD2401800 to GZ), the Pilot Program A Project from the Chinese Academy of Sciences (No. XDA24010206 to ZY), the Foundation of Hubei Hongshan Laboratory (2021hskf013 to GZ and 2021hszd021 to ZY), the National Natural Science Foundation of China (No. 31972779 to GZ), the Youth Innovation Promotion Association of CAS (2020336 to GZ), and the State Key Laboratory of Freshwater Ecology and Biotechnology (2016FBZ05 to ZY).
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.