OP18 - Xanthohumol derivatives as mild mitochondrial uncouplers for treatment of metabolic syndrome

Abstract

Xanthohumol (XN) is a prenylated flavonoid found in hops, beer, and in dietary supplements. There is substantial evidence in the literature that XN improves glucose and lipid metabolism of mammalian cells in vitro, but relatively little is currently known about the potential benefits/risks of chronic exposure to XN in vivo . Even less is known about the underlying mechanisms of action. Using Zucker fa/fa rats and diet-induced obese C57BL/6J mice as models of obesity and metabolic syndrome, we treated animals with XN at three dose levels 6-12 weeks (n=12-16/dose group). The XN-treated animals had significantly lower plasma glucose levels and smaller body weight gain compared to the control groups, while food intake was not affected by treatment. Using an untargeted metabolomics approach, we found a dose-dependent decrease of hepatic triglyceride content and metabolic products of dysfunctional lipid metabolism (medium-chain acylcarnitines, dicarboxy fatty acids, hydroperoxy and hydroxy fatty acids). Taken together, the results indicate that XN improves β-oxidation of fatty acids. Untargeted metabolomics analyses in combination with oxygen consumption measurements of mouse skeletal C2C12 muscle cells treated with XN revealed that it increased basal oxygen consumption and induced an adaptive stress response. Collectively, these findings are consistent with XN acting as a mild mitochondrial uncoupler of oxidative phosphorylation. Because XN has undesired electrophilic and pro-estrogenic properties, we prepared two hydrogenated derivatives of XN that lack electrophilicity and pro-estrogenicity. The derivatives were tested in the diet-induced obese C57BL/6J mice and in the C2C12 cells. They showed comparable activity as the parent XN but at lower doses and concentrations. These data suggest that hydrogenated XN derivatives are promising candidates for further development to treat metabolic syndrome.