Mangiferin stimulates carbohydrate oxidation and protects against metabolic disorders induced by high-fat diets.
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.
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
Pasha
P
Apontes
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
Zhongbo
Z
Liu
Department of Paediatrics, Albert Einstein College of Medicine, Bronx, NY.
Kai
K
Su
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
Outhiriaradjou
O
Benard
Department of Pharmacology, Weill Cornell Medical College, New York, NY.
Dou Y
DY
Youn
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
Xisong
X
Li
Department of Pharmacology, Weill Cornell Medical College, New York, NY.
Wei
W
Li
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
Raihan H
RH
Mirza
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
Claire C
CC
Bastie
Department of Physiology & Biophysics and Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine, Bronx, NY.
Linda A
LA
Jelicks
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY.
Jeffrey E
JE
Pessin
Department of Paediatrics, Albert Einstein College of Medicine, Bronx, NY.
Radhika H
RH
Muzumdar
Department of Pharmacology, Weill Cornell Medical College, New York, NY.
Anthony A
AA
Sauve
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY yuling.chi@einstein.yu.edu.
Yuling
Y
Chi
D000818:Animals; D050260:Carbohydrate Metabolism / Q000187:drug effects*; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects; D007658:Ketone Oxidoreductases / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction / Q000187:drug effects; D019289:Pyruvic Acid / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology*
D044004:Xanthones; C013592:mangiferin; D019289:Pyruvic Acid; D007658:Ketone Oxidoreductases; C053164:pyruvate dehydrogenase (NADP+)