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

Cristobal L Miranda,Jaewoo Choi,Johana S Revel,Valerie Elias ,Christoph Maier ,Ines L Paraiso,Joshua J Hay,Benita S Katzenellenbogen,Ralph L Reed,Paul R Blakemore,Chrissa Kioussi,Russell T Turner,Lea S Ullrich,Urszula T Iwaniec,John A Katzenellenbogen,Jacob Raber,Lance A Johnson,Gerd Bobe,Adrian F Gombart,Oriane De Montgolfier,Jan F Stevens

doi:10.1038/s41598-017-18992-6

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.

Highlights

High-fat diet (HFD) can impair cognitive function[8], including hippocampus-dependent memory in humans[9,10]
Metformin appears to improve insulin signaling by activating 5′-AMP-activated protein kinase (AMPK), but there is no convincing evidence of its effects on dysfunctional lipid metabolism at therapeutic doses[23]
Our studies have shown that treating high-fat diet (HFD)-fed C57BL/6 J mice orally with XN (60 mg/kg/day) reduced their plasma low-density lipoprotein-cholesterol (LDL-c, −80%), interleukin-6 (IL-6, −78%), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) (−52%), leptin (−41%), and plasma levels of the LDL receptor-degrading enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9) (−44%) levels compared to those of vehicle/HFD controls[36]

Summary

Introduction

High-fat diet (HFD) can impair cognitive function[8], including hippocampus-dependent memory in humans[9,10]. MetS has reached epidemic proportions, with an estimated prevalence of 35% among U.S adults in 201222, but no single agent is effective in treating it, and many of the various drugs prescribed have significant risks of adverse effects. We describe the biological activities of two hydrogenated XN derivatives, α,β-dihydro-XN (DXN) and tetrahydro-XN (TXN) (Fig. 1), which lack the α,β-unsaturated ketone and cannot form the estrogenic metabolite 8-PN. Based on the findings from our previous work[36], we selected a dose of 30 mg/kg/day because this dose, which resulted in sub-maximal improvement of MetS-related parameters in XN-treated mice, allows comparison of differences in pharmacological response among XN, DXN, and TXN treatments. In vivo markers of hepatotoxicity, i.e., plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT), were measured in control and treated mice

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Discussion

Conclusion