Key result
A short-term high-fat diet in mice with enhanced cardiac glycolysis increased branched-chain amino acids and upregulated pyruvate dehydrogenase kinase 4 (PDK4) expression.
Why the study?
Metabolic inflexibility increases cardiac reliance on fatty acids leading to deleterious effects, but whether enhancing glucose usage can mitigate these effects under nutrient challenge remains to be clarified.
Enhanced cardiac glycolysis in mice leads to a secondary adaptive response involving increased PDK4 expression to prevent excessive mitochondrial pyruvate oxidation during a high-fat diet.
May reflect adaptive PDK4 response in glycolytic hearts; hypothesis-generating and leaves open human relevance.
The healthy heart has a dynamic capacity to respond and adapt to changes in nutrient availability. Metabolic inflexibility, such as occurs with diabetes, increases cardiac reliance on fatty acids to meet energetic demands, and this results in deleterious effects, including mitochondrial dysfunction, that contribute to pathophysiology. Enhancing glucose usage may mitigate metabolic inflexibility and be advantageous under such conditions. Here, we sought to identify how mitochondrial function and cardiac metabolism are affected in a transgenic mouse model of enhanced cardiac glycolysis (GlycoHi) basally and following a short-term (7-day) high-fat diet (HFD). GlycoHi mice constitutively express an active form of phosphofructokinase-2, resulting in elevated levels of the PFK-1 allosteric activator fructose 2,6-bisphosphate. We report that basally GlycoHi mitochondria exhibit augmented pyruvate-supported respiration relative to fatty acids. Nevertheless, both WT and GlycoHi mitochondria had a similar shift toward increased rates of fatty acid–supported respiration following HFD. Metabolic profiling by GC-MS revealed distinct features based on both genotype and diet, with a unique increase in branched-chain amino acids in the GlycoHi HFD group. Targeted quantitative proteomics analysis also supported both genotype- and diet-dependent changes in protein expression and uncovered an enhanced expression of pyruvate dehydrogenase kinase 4 (PDK4) in the GlycoHi HFD group. These results support a newly identified mechanism whereby the levels of fructose 2,6-bisphosphate promote mitochondrial PDK4 levels and identify a secondary adaptive response that prevents excessive mitochondrial pyruvate oxidation when glycolysis is sustained after a high-fat dietary challenge.
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Newhardt et al. (2019) studied Metabolic inflexibility. Short-term high-fat diet vs. Wild-type mice and basal diet was evaluated on Mitochondrial function, cardiac metabolism, and protein expression. A short-term high-fat diet in mice with enhanced cardiac glycolysis increased branched-chain amino acids and upregulated pyruvate dehydrogenase kinase 4 (PDK4) expression.
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