Xanthohumol Pyrazole Derivative Improves Diet-Induced Obesity and Induces Energy Expenditure in High-Fat Diet-Fed Mice

Ines L Paraiso; Luce M Mattio; Armando Alcázar Magaña; Jaewoo Choi; Layhna S Plagmann; Margaret A Redick; Cristobal L Miranda; Claudia S Maier; Sabrina Dallavalle; Chrissa Kioussi; Paul R Blakemore; Jan F Stevens

doi:10.1021/acsptsci.1c00161

Xanthohumol Pyrazole Derivative Improves Diet-Induced Obesity and Induces Energy Expenditure in High-Fat Diet-Fed Mice

ACS Pharmacol Transl Sci. 2021 Nov 4;4(6):1782-1793. doi: 10.1021/acsptsci.1c00161. eCollection 2021 Dec 10.

Authors

Ines L Paraiso^{1

2}, Luce M Mattio^{1

2

3

4}, Armando Alcázar Magaña^{1

2

3}, Jaewoo Choi¹, Layhna S Plagmann^{1

3}, Margaret A Redick², Cristobal L Miranda^{1

2}, Claudia S Maier³, Sabrina Dallavalle⁴, Chrissa Kioussi², Paul R Blakemore³, Jan F Stevens^{1

2}

Affiliations

¹ Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331, United States.
² Department of Pharmaceutical Sciences, Oregon State University, Corvallis, Oregon 97331, United States.
³ Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, United States.
⁴ Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Celoria 2, Milan 20133, Italy.

Abstract

The energy intake exceeding energy expenditure (EE) results in a positive energy balance, leading to storage of excess energy and weight gain. Here, we investigate the potential of a newly synthesized compound as an inducer of EE for the management of diet-induced obesity and insulin resistance. Xanthohumol (XN), a prenylated flavonoid from hops, was used as a precursor for the synthesis of a pyrazole derivative tested for its properties on high-fat diet (HFD)-induced metabolic impairments. In a comparative study with XN, we report that 4-(5-(4-hydroxyphenyl)-1-methyl-1H-pyrazol-3-yl)-5-methoxy-2-(3-methylbut-2-en-1-yl)benzene-1,3-diol (XP) uncouples oxidative phosphorylation in C2C12 cells. In HFD-fed mice, XP improved glucose tolerance and decreased weight gain by increasing EE and locomotor activity. Using an untargeted metabolomics approach, we assessed the effects of treatment on metabolites and their corresponding biochemical pathways. We found that XP and XN reduced purine metabolites and other energy metabolites in the plasma of HFD-fed mice. The induction of locomotor activity was associated with an increase in inosine monophosphate in the cortex of XP-treated mice. Together, these results suggest that XP, better than XN, affects mitochondrial respiration and cellular energy metabolism to prevent obesity in HFD-fed mice.

Abstract

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