Xanthohumol lowers body weight and fasting plasma glucose in obese male Zucker fa/fa rats
ABSTRACT Obesity contributes to increased risk for several chronic diseases including cardiovascular disease and type 2 diabetes. Xanthohumol, a prenylated flavonoid from hops (Humulus lupulus), was tested for efficacy on biomarkers of metabolic syndrome in 4week old Zucker fa/fa rats, a rodent model of obesity. Rats received daily oral doses of xanthohumol at 0, 1.86, 5.64, and 16.9mg/kg BW for 6weeks. All rats were maintained on a high fat (60% kcal) AIN-93G diet for 3weeks to induce severe obesity followed by a normal AIN-93G (15% kcal fat) diet for the last 3weeks of the study. Weekly food intake and body weight were recorded. Plasma cholesterol, glucose, insulin, triglyceride, and monocyte chemoattractant protein-1 (MCP-1) levels were assessed using commercial assay kits. Plasma and liver tissue levels of XN and its metabolites were determined by liquid-chromatography tandem mass spectrometry. Plasma and liver tissue levels of xanthohumol were similar between low and medium dose groups and significantly (p<0.05) elevated in the highest dose group. There was a dose-dependent effect on body weight and plasma glucose levels. The highest dose group (n=6) had significantly lower plasma glucose levels compared to the control group (n=6) in male but not female rats. There was also a significant decrease in body weight for male rats in the highest dose group (16.9mg/kg BW) compared to rats that received no xanthohumol, which was also not seen for female rats. Plasma cholesterol, insulin, triglycerides, and MCP-1 as well as food intake were not affected by treatment. The findings suggest that xanthohumol has beneficial effects on markers of metabolic syndrome.
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- "In 3T3-L1 adipocytes, Yang et al. reported reduced lipid content and decreased adipocyte marker proteins after incubation with XN . XN also lowers body weight and fasting plasma glucose in obese male Zucker fa/fa rats . Decreased production of the proinflammatory cytokines IL-1 beta, inducible nitric oxide synthase , and IL-12  in LPS-activated macrophages, and reduced monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor alpha concentrations were observed after XN treatment in mouse macrophages and human monocytes . "
ABSTRACT: ScopeXanthohumol (XN), a prenylated antioxidative and anti-inflammatory chalcone from hops, exhibits positive effects on lipid and glucose metabolism. Based on its favorable biological properties, we investigated whether XN attenuates atherosclerosis in western-type diet-fed apolipoprotein-E-deficient (ApoE(-/-)) mice. Methods and resultsXN supplementation markedly reduced plasma cholesterol concentrations, decreased atherosclerotic lesion area, and attenuated plasma concentrations of the proinflammatory cytokine monocyte chemoattractant protein 1. Decreased hepatic triglyceride and cholesterol content, activation of AMP-activated protein kinase, phosphorylation and inactivation of acetyl-CoA carboxylase, and reduced expression levels of mature sterol regulatory element-binding protein (SREBP)-2 and SREBP-1c mRNA indicate reduced lipogenesis in the liver of XN-fed ApoE(-/-) mice. Concomitant induction of hepatic mRNA expression of carnitine palmitoyltransferase-1a in ApoE(-/-) mice-administered XN suggests increased fatty acid beta-oxidation. Fecal cholesterol concentrations were also markedly increased in XN-fed ApoE(-/-) mice compared with mice fed western-type diet alone. Conclusion The atheroprotective effects of XN might be attributed to combined beneficial effects on plasma cholesterol and monocyte chemoattractant protein 1 concentrations and hepatic lipid metabolism via activation of AMP-activated protein kinase.Molecular Nutrition & Food Research 05/2013; 57(10). DOI:10.1002/mnfr.201200794 · 4.91 Impact Factor
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ABSTRACT: Phytoestrogens are a diverse class of non-steroidal compounds that have an affinity for estrogen receptors α and β, for the peroxisome proliferator-activated receptor (PPAR) family and for the aryl hydrocarbon receptor. Examples of phytoestrogens include prenylated flavonoids, isoflavones, coumestans and lignans. Many phytoestrogens counteract the cellular derailments that are responsible for the development of metabolic syndrome. Here we propose a mechanism of action which is based on five pillars/principles. First, phytoestrogens are involved in the downregulation of pro-inflammatory cytokines, such as COX-2 and iNOS, by activating PPAR and by inhibiting IκB activation. Second, they increase reverse cholesterol transport, which is mediated by PPARγ. Third, phytoestrogens increase insulin sensitivity, which is mediated via PPARα. Fourth, they exert antioxidant effects by activating antioxidant genes through KEAP. Fifth, phytoestrogens increase energy expenditure by affecting AMP-activated kinase signalling cascades, which are responsible for the inhibition of adipogenesis. In addition to these effects, which have been demonstrated in vivo and in clinical trials, other effects, such as eNOS activation, may also be important. Some plant extracts from soy, red clover or licorice can be described as panPPAR activators. Fetal programming for metabolic syndrome has been hypothesized; thus, the consumption of dietary phytoestrogens during pregnancy may be relevant. Extracts from soy, red clover or licorice oil have potential as plant-derived medicines that could be used to treat polycystic ovary syndrome, a disease linked to hyperandrogenism and obesity, although clinical trials have not yet been conducted. Phytoestrogens may help prevent metabolic syndrome, although intervention studies will be always be ambiguous, because physical activity and reduced calorie consumption also have a significant impact. Nevertheless, extracts rich in phytoestrogens may be an alternative treatment or may complement conventional treatment for diseases linked with metabolic syndrome.The Journal of steroid biochemistry and molecular biology 01/2013; 139. DOI:10.1016/j.jsbmb.2012.12.009 · 4.05 Impact Factor
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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 electrophilicty 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.Journal of Biological Chemistry 05/2013; 288(26). DOI:10.1074/jbc.M112.445452 · 4.57 Impact Factor