Farnesoid X receptor is an effective target for modulating lipid accumulation in grass carp, Ctenopharyngodon idella

Abstract Excessive lipid accumulation in grass carp (Ctenopharyngodon idella) is one of the greatest challenges in the aquaculture industry. Farnesoid X receptor (FXR) is being increasingly recognized as an important node in the regulation of fat content in mammals; however, its role in fish remains unknown. Here, we explored the fat-regulation function of FXR in juvenile grass carp (9.89 ± 0.20 g) by supplementing feed with the FXR agonist GW4064 and FXR inhibitor glycine-β-muricholic acid (Gly-β-MCA). Moreover, to further explore FXR regulation by gut microbiota, an antibiotic mixture (ABM; 200 mg/kg ampicillin, 200 mg/kg neomycin, 200 mg/kg gentamicin, 200 mg/kg metronidazole, and 10 mg/kg vancomycin) was also administered in the diet. Pharmaceutical activation of FXR by GW4064 significantly decreased hepatopancreas triglyceride and cholesterol content, whereas FXR inhibition by Gly-β-MCA administration significantly increased the hepatopancreas index, intraperitoneal fat index, hepatopancreas triglyceride, and cholesterol levels of grass carp. Interestingly, diversity and community evenness of the gut microbiota increased and the intestinal activity of bile salt hydrolase decreased in ABM-fed fish. Dietary ABM also inhibited FXR signalling gene expression and increased lipid accumulation in the hepatopancreas of grass carp. To investigate the molecular mechanism, we explored the hepatopancreatic transcriptome in fish fed either Gly-β-MCA or ABM. These two treatments shared seven lipid metabolism-annotated differentially expressed genes, indicating increased lipid synthesis and lipid droplet formation capacity in the two groups. Overall, our study demonstrates that FXR tends to play a negative regulatory role in lipid accumulation in grass carp and is a potential target for regulating lipid accumulation.