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

Cristobal L. Miranda, Lance A. Johnson, Oriane De Montgolfier, Valerie D. Elias, Lea S. Ullrich, Joshua J. Hay, Ines L. Paraiso, Jaewoo Choi, Ralph L. Reed, Johana S. Revel, Chrissa Kioussi, Gerd Bobe, Urszula T. Iwaniec, Russell T. Turner, Benita S Katzenellenbogen, John A. Katzenellenbogen, Paul R. Blakemore, Adrian F. Gombart, Claudia S. Maier, Jacob Raber & 1 others Jan F. Stevens

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number613
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Obese Mice
High Fat Diet
Insulin Resistance
Cognitive Dysfunction
xanthohumol
Humulus
Glucose Intolerance
Myoblasts
Liver
Leptin
Inbred C57BL Mouse
Lipid Metabolism
Flavonoids
Estrogen Receptors
Respiration
Estrogens
Animal Models
Obesity
Glucose
Muscles

ASJC Scopus subject areas

  • General

Cite this

Miranda, C. L., Johnson, L. A., De Montgolfier, O., Elias, V. D., Ullrich, L. S., Hay, J. J., ... Stevens, J. F. (2018). Non-estrogenic Xanthohumol Derivatives Mitigate Insulin Resistance and Cognitive Impairment in High-Fat Diet-induced Obese Mice. Scientific Reports, 8(1), [613]. https://doi.org/10.1038/s41598-017-18992-6

Non-estrogenic Xanthohumol Derivatives Mitigate Insulin Resistance and Cognitive Impairment in High-Fat Diet-induced Obese Mice. / Miranda, Cristobal L.; Johnson, Lance A.; De Montgolfier, Oriane; Elias, Valerie D.; Ullrich, Lea S.; Hay, Joshua J.; Paraiso, Ines L.; Choi, Jaewoo; Reed, Ralph L.; Revel, Johana S.; Kioussi, Chrissa; Bobe, Gerd; Iwaniec, Urszula T.; Turner, Russell T.; Katzenellenbogen, Benita S; Katzenellenbogen, John A.; Blakemore, Paul R.; Gombart, Adrian F.; Maier, Claudia S.; Raber, Jacob; Stevens, Jan F.

In: Scientific Reports, Vol. 8, No. 1, 613, 01.12.2018.

Research output: Contribution to journalArticle

Miranda, 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 2018, 'Non-estrogenic Xanthohumol Derivatives Mitigate Insulin Resistance and Cognitive Impairment in High-Fat Diet-induced Obese Mice', Scientific Reports, vol. 8, no. 1, 613. https://doi.org/10.1038/s41598-017-18992-6
Miranda, Cristobal L. ; Johnson, Lance A. ; De Montgolfier, Oriane ; Elias, Valerie D. ; Ullrich, Lea S. ; Hay, Joshua J. ; Paraiso, Ines L. ; Choi, Jaewoo ; Reed, Ralph L. ; Revel, Johana S. ; Kioussi, Chrissa ; Bobe, Gerd ; Iwaniec, Urszula T. ; Turner, Russell T. ; Katzenellenbogen, Benita S ; Katzenellenbogen, John A. ; Blakemore, Paul R. ; Gombart, Adrian F. ; Maier, Claudia S. ; Raber, Jacob ; Stevens, Jan F. / Non-estrogenic Xanthohumol Derivatives Mitigate Insulin Resistance and Cognitive Impairment in High-Fat Diet-induced Obese Mice. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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T1 - Non-estrogenic Xanthohumol Derivatives Mitigate Insulin Resistance and Cognitive Impairment in High-Fat Diet-induced Obese Mice

AU - Miranda, Cristobal L.

AU - Johnson, Lance A.

AU - De Montgolfier, Oriane

AU - Elias, Valerie D.

AU - Ullrich, Lea S.

AU - Hay, Joshua J.

AU - Paraiso, Ines L.

AU - Choi, Jaewoo

AU - Reed, Ralph L.

AU - Revel, Johana S.

AU - Kioussi, Chrissa

AU - Bobe, Gerd

AU - Iwaniec, Urszula T.

AU - Turner, Russell T.

AU - Katzenellenbogen, Benita S

AU - Katzenellenbogen, John A.

AU - Blakemore, Paul R.

AU - Gombart, Adrian F.

AU - Maier, Claudia S.

AU - Raber, Jacob

AU - Stevens, Jan F.

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N2 - 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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