Xanthohumol and its derivatives mitigate metabolic syndrome and associated cognitive impairments in obese C57BL/6J mice

 

Xanthohumol (XN) is a prenylated flavonoid found in hops (Humulus lupulus) and beer. It has received increasing attention in recent years due to its reported beneficial effects on dysfunctional glucose and lipid metabolism in rodent models of metabolic syndrome (MetS) [1,2]. Gut microbial metabolism of XN yields the estrogenic metabolite, 8-prenylnaringenin [3], which is a potential health concern in the development of XN as a dietary supplement for prevention or treatment of MetS. We approached this problem by reducing the double bond of XN's α,β-unsaturated keto moiety to yield the hydrogenated derivatives, α,β-dihydro-XN (DXN) and tetrahydroxanthohumol (TXN), which cannot be metabolically converted into 8-prenylnaringenin. Forty eight C57BL/6J mice were divided into four groups of 12 mice and fed a high-fat diet containing vehicle (0 mg/kg), or XN, or DXN, or TXN (providing a daily dose of 30 mg/kg body weight), for 14 weeks. Mice given DXN and TXN showed higher plasma levels and greater improvement of impaired glucose tolerance compared to XN at 4 and 11 weeks. DXN was detected in liver samples, indicating that XN is reduced by an enoate reductase of gut microbial origin because DXN was not detected in germ-free mice. At 13 weeks, we also assessed the effects of XN, DXN and TXN on cognitive performance in the water maze as described by Johnson et al. [4]. Mice treated with XN and DXN showed better hippocampus-dependent spatial learning than vehicle-treated mice. Mice treated with XN, DXN, and TXN showed spatial memory retention, while vehicle-treated mice did not. These data demonstrate that DXN and TXN exert greater size effects on markers of MetS, presumably due to their greater bioavailability, compared to XN. By contrast, XN showed greater improvement in memory retention compared to DXN and TXN, indicating that the observed improvement of dysfunctional glucose metabolism cannot fully account for the improvement of impaired cognitive function.

Acknowledgments: This work was supported by the Linus Pauling Institute, the OSU College of Pharmacy, Hopsteiner, Inc., New York, the OSU Foundation Buhler-Wang Research Fund, the National Science Foundation, and the National Institutes of Health (Grant R01AT009168).

Keywords: Xanthohumol, Humulus lupulus, metabolic syndrome, cognitive performance.

References:

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