TitleA metabolomics-driven elucidation of the anti-obesity mechanisms of xanthohumol.
Publication TypeJournal Article
Year of Publication2013
AuthorsKirkwood JS, Legette LCL, Miranda CL, Jiang Y, Stevens JF
JournalJ Biol Chem
Date Published2013 Jun 28
KeywordsAnimals, Anti-Obesity Agents, Cell Line, Chromatography, Liquid, Disease Models, Animal, Female, Flavonoids, Ion Channels, Male, Mass Spectrometry, Metabolic Syndrome, Metabolomics, Mice, Mitochondrial Proteins, Muscle Cells, Oxidative Stress, Propiophenones, Rats, Rats, Zucker, Reactive Oxygen Species, Time Factors, Uncoupling Protein 1

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.

Alternate JournalJ. Biol. Chem.
PubMed ID23673658
PubMed Central IDPMC3696674
Grant ListP30 ES00210 / ES / NIEHS NIH HHS / United States
P30ES000210 / ES / NIEHS NIH HHS / United States
S10RR027878 / RR / NCRR NIH HHS / United States
R21 AT005294 / AT / NCCIH NIH HHS / United States
S10 RR027878 / RR / NCRR NIH HHS / United States
R21AT005294 / AT / NCCIH NIH HHS / United States
P30 ES000210 / ES / NIEHS NIH HHS / United States