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

Abstract

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.

High dietary fat intake increases fat oxidation and reduces skeletal muscle mitochondrial respiration in trained humans

“…Decreased respiration observed after the addition of octanoylcarnitine and pyruvate is in line with previous studies that have reported that HFAT diets reduce the amount of PDH, in its active form (PDHa), and PDHa activity at rest, but not after a moderate CHO diet (21). Alterations in PDH activity have additionally been identified as a mechanism that underlies the regulation of metabolic flexibility in isolated rodent skeletal muscle mitochondria in response to altered substrate availability induced by high‐fat feeding (22). In addition, the reduction in respiration after 5 d of HFAT diet persisted after uncoupling (ETS CI + CII + ETF, and ETS CII), which suggests that the functional reductions in respiration occurred either at the level of CI/CII or downstream at CIII/ CIV, but not at complex V (ATP synthase).…”

Acute and chronic changes in rat soleus muscle after high-fat high-sucrose diet

“…Recent evidence demonstrates that 12 weeks of high‐fat or high‐sucrose feeding impairs mitochondrial function in glycolytic quadriceps muscles of rats (Jørgensen et al. ). In the present studies, SDH mRNA levels were increased after 2 and 4 weeks of HFS diet, suggesting a short‐term compensatory increase in oxidative capacity with metabolic disturbance.…”

Decreased Metabolic Flexibility in Skeletal Muscle of Rat Fed with a High-Fat Diet Is Recovered by Individual CLA Isomer Supplementation via Converging Protective Mechanisms

“…Adiponectin acts via the activation of peroxisome proliferator-activated receptors-alpha (PPAR-α) while leptin through direct activation of adenosine monophosphate-activated protein kinase (AMPK) [6]. Interestingly, isolated skeletal muscle mitochondria from rats fed high-sugar or high-fat diets showed reduced metabolic flexibility, indicating that substrate preference is independent of cytosolic-mitochondrial communication and in fact is a consequence of inherent mitochondrial biochemical network interactions [7]. Intriguingly, several food components, along with diet and exercise, have been indicated as a promising approach to manage the main clinical complications of metabolic syndrome [8], but their efficacy in modulating metabolic flexibility has been only partially investigated.…”