TitleXanthohumol improves cognition in farnesoid X receptor-deficient mice on a high-fat diet.
Publication TypeJournal Article
Year of Publication2022
AuthorsKundu P, Paraiso IL, Choi J, Miranda CL, Kioussi C, Maier CS, Bobe G, Stevens JF, Raber J
JournalDis Model Mech
Date Published2022 Nov 01
KeywordsAnimals, Bile Acids and Salts, Ceramides, Cognition, Diet, High-Fat, Diglycerides, Liver, Male, Mice, Mice, Inbred C57BL

Xanthohumol (XN) improves cognition of wild-type rodents on a high-fat diet (HFD). Bile acids and ceramide levels in the liver and hippocampus might be linked to these effects. XN modulates activity of the nuclear farnesoid X receptor (FXR; also known as NR1H4), the primary receptor 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-/-, respectively) on an HFD or an 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-type), reversal learning in males (specifically wild-type and FXRIntestine-/- mutant) and 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 longer-chain ceramide and hexaceramide levels were linked to improved cognitive performance. Thus, the beneficial sex-dependent cognitive effects of XN are linked to changes in hippocampal diacylglycerol and ceramide levels. This article has an associated First Person interview with the first author of the paper.

Alternate JournalDis Model Mech
PubMed ID36353888
PubMed Central IDPMC9713832
Grant ListT32 AG055378 / AG / NIA NIH HHS / United States
S10 RR022589 / RR / NCRR NIH HHS / United States
RF1 AG059088 / AG / NIA NIH HHS / United States
S10 RR027878 / RR / NCRR NIH HHS / United States