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Sci Rep. 2018 Jan 12;8(1):613. doi: 10.1038/s41598-017-18992-6.

Non-estrogenic Xanthohumol Derivatives Mitigate Insulin Resistance and Cognitive Impairment in High-Fat Diet-induced Obese Mice.

Author information

1
Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA.
2
Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, 97331, USA.
3
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA.
4
Department of Chemistry, Oregon State University, Corvallis, OR, 97331, USA.
5
Department of Animal & Rangeland Sciences, Oregon State University, Corvallis, OR, 97331, USA.
6
Skeletal Biology Laboratory, School of Biological and Population Health Sciences, College of Public Health and Human Sciences, Oregon State University, Corvallis, OR, 97331, USA.
7
Departments of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
8
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
9
Department of Biochemistry & Biophysics, Oregon State University, Corvallis, OR, 97331, USA.
10
Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, 97331, USA. raberj@ohsu.edu.
11
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA. raberj@ohsu.edu.
12
Departments of Neurology and Radiation Medicine, Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA. raberj@ohsu.edu.
13
Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA. fred.stevens@oregonstate.edu.
14
Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, 97331, USA. fred.stevens@oregonstate.edu.

Abstract

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.

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