TitleNon-estrogenic Xanthohumol Derivatives Mitigate Insulin Resistance and Cognitive Impairment in High-Fat Diet-induced Obese Mice.
Publication TypeJournal Article
Year of Publication2018
AuthorsMiranda CL, Johnson LA, de Montgolfier O, Elias VD, Ullrich LS, Hay JJ, Paraiso IL, Choi J, Reed RL, Revel JS, Kioussi C, Bobe G, Iwaniec UT, Turner RT, Katzenellenbogen BS, Katzenellenbogen JA, Blakemore PR, Gombart AF, Maier CS, Raber J, Stevens JF
JournalSci Rep
Date Published2018 Jan 12

Xanthohumol (XN), a prenylated flavonoid from hops, improves dysfunctional glucose and lipid metabolism in animal models of metabolic syndrome (MetS). However, its metabolic transformation into the estrogenic metabolite, 8-prenylnaringenin (8-PN), poses a potential health concern for its use in humans. To address this concern, we evaluated two hydrogenated derivatives, α,β-dihydro-XN (DXN) and tetrahydro-XN (TXN), which showed negligible affinity for estrogen receptors α and β, and which cannot be metabolically converted into 8-PN. We compared their effects to those of XN by feeding C57BL/6J mice a high-fat diet (HFD) containing XN, DXN, or TXN for 13 weeks. DXN and TXN were present at higher concentrations than XN in plasma, liver and muscle. Mice administered XN, DXN or TXN showed improvements of impaired glucose tolerance compared to the controls. DXN and TXN treatment resulted in a decrease of HOMA-IR and plasma leptin. C2C12 embryonic muscle cells treated with DXN or TXN exhibited higher rates of uncoupled mitochondrial respiration compared to XN and the control. Finally, XN, DXN, or TXN treatment ameliorated HFD-induced deficits in spatial learning and memory. Taken together, DXN and TXN could ameliorate the neurocognitive-metabolic impairments associated with HFD-induced obesity without risk of liver injury and adverse estrogenic effects.

Alternate JournalSci Rep
PubMed ID29330372
PubMed Central IDPMC5766630
Grant ListR01 AT009168 / AT / NCCIH NIH HHS / United States
T32 HL094294 / HL / NHLBI NIH HHS / United States
R01 DK015556 / DK / NIDDK NIH HHS / United States
S10 RR027878 / RR / NCRR NIH HHS / United States
T32 ES007060 / ES / NIEHS NIH HHS / United States