Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Int J Mol Sci. 2018 Jan 9;19(1):201. doi: 10.3390/ijms19010201.
One of the main causes of hyperglycemia is inefficient or impaired glucose utilization by skeletal muscle, which can be exacerbated by chronic high caloric intake. Previously, we identified a natural compound, mangiferin (MGF) that improved glucose utilization in high fat diet (HFD)-induced insulin resistant mice. To further identify the molecular mechanisms of MGF action on glucose metabolism, we conducted targeted metabolomics and transcriptomics studies of glycolyic and mitochondrial bioenergetics pathways in skeletal muscle. These data revealed that MGF increased glycolytic metabolites that were further augmented as glycolysis proceeded from the early to the late steps. Consistent with an MGF-stimulation of glycolytic flux there was a concomitant increase in the expression of enzymes catalyzing glycolysis. MGF also increased important metabolites in the tricarboxylic acid (TCA) cycle, such as α-ketoglutarate and fumarate. Interestingly however, there was a reduction in succinate, a metabolite that also feeds into the electron transport chain to produce energy. MGF increased succinate clearance by enhancing the expression and activity of succinate dehydrogenase, leading to increased ATP production. At the transcriptional level, MGF induced mRNAs of mitochondrial genes and their transcriptional factors. Together, these data suggest that MGF upregulates mitochondrial oxidative capacity that likely drives the acceleration of glycolysis flux.
高血糖的一个主要原因是骨骼肌对葡萄糖的利用效率低下或受损，而长期高卡路里摄入会加剧这种情况。此前，我们发现了一种天然化合物芒果苷（MGF），它可以改善高脂肪饮食（HFD）诱导的胰岛素抵抗小鼠的葡萄糖利用。为了进一步确定 MGF 对葡萄糖代谢作用的分子机制，我们对骨骼肌的糖酵解和线粒体生物能学途径进行了靶向代谢组学和转录组学研究。这些数据显示，MGF 增加了糖酵解代谢物，随着糖酵解从早期到晚期的进行，这些代谢物进一步增加。与 MGF 刺激糖酵解通量一致，催化糖酵解的酶的表达也随之增加。MGF 还增加了三羧酸（TCA）循环中的重要代谢物，如α-酮戊二酸和延胡索酸。有趣的是，琥珀酸减少了，琥珀酸是一种也能进入电子传递链产生能量的代谢物。MGF 通过增强琥珀酸脱氢酶的表达和活性来增加琥珀酸的清除率，从而增加 ATP 的产生。在转录水平上，MGF 诱导了线粒体基因及其转录因子的 mRNA。总的来说，这些数据表明，MGF 上调了线粒体氧化能力，这可能推动了糖酵解通量的加速。
