Abstract
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.
Highlights
Pyruvate enters the tricarboxylic acid (TCA) cycle mainly via two possible pathways, pyruvate decarboxylation by pyruvate dehydrogenase (PDH) to form acetyl-CoA, whose subsequent metabolites feed into the electron transport chain (ETC) for mitochondrial respiration to produce energy, or carboxylation by pyruvate carboxylase to form oxaloacetate, which participates in TCA cycle anaplerosis [1,2]
Based on the reversibility of catabolic reactions, the TCA cycle is thought to operate in two sequential segments, the first being from acetyl-CoA until α-KG and the second being from α-KG to oxaloacetate [3]
We have demonstrated that MGF activates PDH, which presumably directs glucose metabolism to the mitochondrial oxidative processes
Summary
The last one generates pyruvate, a key metabolic branching point at which carbohydrate metabolism either goes through the anaerobic pathway to form lactate or the aerobic pathway to generate energy in mitochondria. While formation of lactate is a relatively fast way for glucose metabolism, the oxidative metabolism in mitochondria produces much more energy and is a more effective pathway to utilize carbohydrate nutrients and eliminate energy storage in form of, for instance, fat. Pyruvate enters the TCA cycle mainly via two possible pathways, pyruvate decarboxylation by pyruvate dehydrogenase (PDH) to form acetyl-CoA, whose subsequent metabolites feed into the ETC for mitochondrial respiration to produce energy, or carboxylation by pyruvate carboxylase to form oxaloacetate, which participates in TCA cycle anaplerosis [1,2]. Based on the reversibility of catabolic reactions, the TCA cycle is thought to operate in two sequential segments, the first being from acetyl-CoA until α-KG and the second being from α-KG to oxaloacetate [3]
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