A Metabolomics-driven Elucidation of the Anti-obesity Mechanisms of Xanthohumol
A Metabolomics-driven Elucidation of the Anti-obesity Mechanisms of Xanthohumol
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DOI：
10.1074/jbc.m112.445452
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发表时间：
2013-06-28
影响因子：
4.8
通讯作者：
Stevens, Jan F.
中科院分区：
文献类型：
--
作者：
Kirkwood, Jay S.;Legette, LeeCole L.;Stevens, Jan F.
轻度的线粒体解偶联会增加能量消耗，减少活性氧（ROS）的产生。激活细胞，适应性应激反应途径可以导致增强的能力，以减少氧化损伤。总之，这些策略针对的是能量失衡和氧化应激，这两者都是肥胖和2型糖尿病等相关疾病的潜在因素。在这里，我们描述了代谢组学驱动的努力，以揭示黄腐酚（XN）的抗肥胖机制(s)，黄腐酚是一种来自啤酒花的烯酰化类黄酮。XN对肥胖Zucker大鼠空腹血浆代谢组学分析显示，功能失调脂肪酸氧化产物和ROS减少，这促使我们探索XN对肌肉细胞生物能量学的影响。在低微摩尔浓度下，XN急剧增加了几种不同细胞类型的非偶联呼吸，包括肌细胞。四羟基茴香酚还能增加呼吸，这表明亲电性并没有起作用。在较高浓度下，XN以ros依赖的方式抑制呼吸。在肌细胞中，时间过程代谢组学揭示了谷胱甘肽循环的急性激活和谷胱甘肽合成的长期诱导，以及表明短期细胞应激升高和协调一致的适应性反应的其他一些变化。基于这些发现，我们假设XN可能通过线粒体解偶联和应激反应诱导，至少在一定程度上改善代谢综合征。此外，时间过程代谢组学似乎是揭示应激反应期间发生的代谢事件的有效策略。
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.