Your mitochondria are what you eat: a high‐fat or a high‐sucrose diet eliminates metabolic flexibility in isolated mitochondria from rat skeletal muscle

Extreme diets consisting of either high fat (HF) or high sucrose (HS) may lead to insulin resistance in skeletal muscle, often associated with mitochondrial dysfunction. However, it is not known if these diets alter normal interactions of pyruvate and fatty acid oxidation at the level of the mitochondria. Here, we report that rat muscle mitochondria does show the normal Randle‐type fat‐carbohydrate interaction seen in vivo. The mechanism behind this metabolic flexibility at the level of the isolated mitochondria is a regulation of the flux‐ratio: pyruvate dehydrogenase (PDH)/β‐oxidation to suit the actual substrate availability, with the PDH flux as the major point of regulation. We further report that this regulatory mechanism of carbohydrate‐fat metabolic interaction surprisingly is lost in mitochondria obtained from animals exposed for 12 weeks to a HF‐ or a HS diet as compared to rats given a normal chow diet. The mechanism seems to be a loss of the PDH flux decrease seen in controls, when fatty acid is supplied as substrate in addition to pyruvate, and vice versa for the supply of pyruvate as substrate to mitochondria oxidizing fatty acid. Finally, we report that the calculated TCA flux in the isolated mitochondria under these circumstances shows a significant reduction (~50%) after the HF diet and an even larger reduction (~75%) after the HS diet, compared with the chow group. Thus, it appears that obesogenic diets as those applied here have major influence on key metabolic performance of skeletal muscle mitochondria. Isolated rat muscle mitochondria show a normal Randle‐type fat‐carbohydrate interaction. The mechanisms behind this metabolic flexibility at the level of the isolated mitochondria seem to be a regulation of the flux‐ratio: pyruvate dehydrogenase (PDH)/β‐oxidation to suit the actual substrate availability, with the PDH flux as the major point of regulation. This interaction is lost, however, when rats are exposed to long term high‐fat or high‐sucrose diet.