Cognitive effects of Xanthohumol in wild-type and mutant mice lacking FXR in the intestine or liver on a high-fat diet.

Xanthohumol (XN) improves cognition of wild-type rodents on a high fat diet. Bile acids and ceramide levels in the liver and hippocampus might be linked to these effects. XN modulates activity of the nuclear farsenoid X receptor (FXR), the primary receptor family for bile acids. To determine the role of FXR in the liver and intestine in mediating the effects of XN on cognitive performance, mice with intestine- and liver-specific FXR-ablation (FXRIntestine-/- and FXRLiver-/-) on a HFD or a HFD containing XN were cognitively tested. XN improved cognitive performance in a genotype- and sex- dependent manner with improved task learning in females (specifically wild-types), in reversal learning in males (specifically wild-type and FXRIntestine-/- mutants), and in spatial learning (both sexes). XN increased hippocampal diacylglycerol and sphingomyelin levels in females but decreased them in males. XN increased the ratio of shorter-chain to longer chain ceramides and hexaceramides. Higher diacylglycerol and lower of longer chain ceramides and hexaceramides levels were linked to improved cognitive performance. Thus, beneficial sex-dependent cognitive effects of XN are linked to changes in hippocampal diacylglycerol and ceramide levels.