High Fat Diet Impairs Mitochondrial ADP Sensitivity and Attenuates Respiration in the Presence of Submaximal, but Not Maximal, ADP Concentrations

The consumption of a high fat (HF) diet is a major contributor of ectopic lipid accumulation in skeletal muscle and insulin resistance. While the underlying mechanisms are not well‐defined, mitochondrial dysfunction, including lower ADP sensitivity through the voltage dependent anion channel (VDAC)/adenine nucleotide transport (ANT) axis, has been implicated in this process. It is currently unknown how a HF diet impairs mitochondrial function, however, lipid moieties (palmitoyl‐CoA; P‐CoA) have been shown to inhibit ANT and reduce ADP sensitivity in situ . Therefore, lipid accumulation following a HF diet could promote inhibition on ANT, explaining these mitochondrial abnormalities and possibly insulin resistance. Since we have previously shown mitochondrial creatine kinase (Mi‐CK) knockout (KO) mice have greater ADP sensitivity through the VDAC/ANT axis when challenged by exercise, a situation that also increases intramuscular lipid supply, we determined whether this would be protective against HF‐induced mitochondrial dysfunction and insulin resistance. Mi‐CK wildtype (WT) and KO mice were fed a control (CON) or HF diet (60% fat) for 4 weeks. High‐resolution respirometry was used to assess ADP sensitivity in the presence or absence of P‐CoA in permeabilized muscle fibres, glucose‐tolerance tests were performed, and western blotting was used to determine VDAC and ANT protein content. Our results show on a CON diet that ADP sensitivity in the absence of P‐CoA was not affected by ablating Mi‐CK, while in contrast these mice displayed attenuated P‐CoA‐mediated inhibition of ADP sensitivity. Therefore, we determined if KO mice would be protected from HF diet impairments in ADP sensitivity, and insulin resistance, through improved ADP transport. However, regardless of genotype, consumption of a HF diet resulted in modest reductions in ADP sensitivity in the absence of P‐CoA, which corresponded with reduced insulin sensitivity. This occurred in the absence of altered VDAC or ANT protein content, highlighting external regulation of these proteins following a HF diet. While Mi‐CK KO mice were not protected from HF diet‐induced insulin resistance, this may occur because the improved ADP sensitivity in the presence of P‐CoA was lost during the HF diet. Altogether, these data demonstrate that reductions in ADP sensitivity may be an early event contributing to insulin resistance, while an increase in intramuscular P‐CoA concentrations and an improved sensitivity to P‐CoA inhibition may exacerbate this response. Support or Funding Information Natural Sciences and Engineering Research Council of Canada; Canadian Foundation for Innovation/Ontario Research Fund.

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