TXN, a Xanthohumol Derivative, Attenuates High-Fat Diet Induced Hepatic Steatosis by Antagonizing PPARγ

We previously reported xanthohumol (XN), and its synthetic derivative tetrahydro-XN (TXN) attenuates high-fat diet (HFD) induced obesity and metabolic syndrome in C57BL/6J mice. The objective of the current study was to determine the effect of XN and TXN on lipid accumulation in the liver. Non-supplemented mice were unable to adapt their caloric intake to 60% HFD, resulting in obesity and hepatic steatosis; however, TXN reduced weight gain and decreased hepatic steatosis. Liver transcriptomics indicated TXN might antagonize lipogenic PPARγ actionsin vivo. XN and TXN inhibited rosiglitazone-induced 3T3-L1 cell differentiation concomitant with decreased expression of lipogenesis-related genes. A PPARγ competitive binding assay showed XN and TXN bind to PPARγ with an IC₅₀similar to pioglitazone and 8-10 times stronger than oleate. Molecular docking simulations demonstrated XN and TXN bind in the PPARγ ligand-binding domain pocket. Our findings are consistent with XN and TXN acting as antagonists of PPARγ.