title: A metabolomics-driven elucidation of the anti-obesity mechanisms of xanthohumol.
abstract: Mild, mitochondrial uncoupling increases energy expenditure and can reduce the generation of reactive oxygen species (ROS). Activation of cellular, adaptive stress response pathways can result in an enhanced capacity to reduce oxidative damage. Together, these strategies target energy imbalance and oxidative stress, both underlying factors of obesity and related conditions such as type 2 diabetes. Here we describe a metabolomics-driven effort to uncover the anti-obesity mechanism(s) of xanthohumol (XN), a prenylated flavonoid from hops. Metabolomics analysis of fasting plasma from obese, Zucker rats treated with XN revealed decreases in products of dysfunctional fatty acid oxidation and ROS, prompting us to explore the effects of XN on muscle cell bioenergetics. At low micromolar concentrations, XN acutely increased uncoupled respiration in several different cell types, including myocytes. Tetrahydroxanthohumol also increased respiration, suggesting electrophilicity did not play a role. At higher concentrations, XN inhibited respiration in a ROS-dependent manner. In myocytes, time course metabolomics revealed acute activation of glutathione recycling and long term induction of glutathione synthesis as well as several other changes indicative of short term elevated cellular stress and a concerted adaptive response. Based on these findings, we hypothesize that XN may ameliorate metabolic syndrome, at least in part, through mitochondrial uncoupling and stress response induction. In addition, time course metabolomics appears to be an effective strategy for uncovering metabolic events that occur during a stress response.
authors.affiliation: Linus Pauling Institute and the Department of Pharmaceutical Sciences, Oregon State University, Corvallis, Oregon 97331, USA.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Kirkwood
authors.forename: LeeCole L
authors.initials: LL
authors.lastname: Legette
authors.forename: Cristobal L
authors.initials: CL
authors.lastname: Miranda
authors.forename: Yuan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Jan F
authors.initials: JF
authors.lastname: Stevens
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D002460:Cell Line; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D005260:Female; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D024821:Metabolic Syndrome / Q000188:drug therapy; D055432:Metabolomics; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism; D032342:Muscle Cells / Q000166:cytology; D018384:Oxidative Stress; D011427:Propiophenones / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species; D013997:Time Factors; D000071256:Uncoupling Protein 1
chemical_list: D019440:Anti-Obesity Agents; D005419:Flavonoids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D011427:Propiophenones; D017382:Reactive Oxygen Species; D000071256:Uncoupling Protein 1; C104536:xanthohumol
keywords: Flavonoids; Mass Spectrometry (MS); Metabolism; Metabolomics; Obesity