Excessive
dietary fat intake causes systemic metabolic toxicity, manifested in
weight gain,
hyperglycemia, and
insulin resistance. In addition,
carbohydrate utilization as a fuel is substantially inhibited. Correction or reversal of these effects during high-fat diet (HFD) intake is of exceptional interest in light of widespread occurrence of diet-associated metabolic disorders in global human populations. Here we report that
mangiferin (MGF), a natural compound (the predominant constituent of
Mangifera indica extract from the plant that produces mango), protected against HFD-induced
weight gain, increased aerobic mitochondrial capacity and thermogenesis, and improved
glucose and
insulin profiles. To obtain mechanistic insight into the basis for these effects, we determined that mice exposed to an HFD combined with MGF exhibited a substantial shift in respiratory quotient from
fatty acid toward
carbohydrate utilization. MGF treatment significantly increased
glucose oxidation in muscle of HFD-fed mice without changing
fatty acid oxidation. These results indicate that MGF redirects fuel utilization toward
carbohydrates. In cultured C2C12 myotubes, MGF increased
glucose and
pyruvate oxidation and
ATP production without affecting
fatty acid oxidation, confirming in vivo and ex vivo effects. Furthermore, MGF inhibited anaerobic metabolism of
pyruvate to
lactate but enhanced
pyruvate oxidation. A key target of MGF appears to be
pyruvate dehydrogenase, determined to be activated by MGF in a variety of assays. These findings underscore the therapeutic potential of activation of
carbohydrate utilization in correction of
metabolic syndrome and highlight the potential of MGF to serve as a model compound that can elicit fuel-switching effects.