Skeletal muscle mitochondrial protein synthesis is regulated in part by insulin. The development of insulin resistance with diet-induced obesity may therefore contribute to impairments to protein synthesis and decreased mitochondrial respiration. Yet, the impact of diet-induced obesity and insulin resistance on mitochondrial energetics is controversial with reports varying from decreases to increases in mitochondrial respiration. We investigated the impact of changes in insulin sensitivity on long-term rates of mitochondrial protein synthesis as a mechanism for changes to mitochondrial respiration in skeletal muscle. Insulin resistance was induced in C57BL/6J mice using 4 weeks of high-fat compared with low-fat diet. For 8 additional weeks, diets were enriched in pioglitazone to restore insulin sensitivity as compared with non-enriched control low-fat or high-fat diet. Skeletal muscle mitochondrial protein synthesis was measured using deuterium oxide labeling during weeks 10 to 12. High-resolution respirometry was performed using palmitoyl-L-carnitine, glutamate+malate and glutamate+malate+succinate as substrates for mitochondria isolated from quadriceps. Mitochondrial protein synthesis and palmitoyl-L-carnitine oxidation were increased in mice consuming high-fat diet, regardless of differences in insulin sensitivity with pioglitazone treatment. There was no effect of diet or pioglitazone treatment on ADP-stimulated respiration or H₂O₂ emission using glutamate+malate or glutamate+malate+succinate. The results demonstrate no impairments to mitochondrial protein synthesis or respiration following induction of insulin resistance. Instead, mitochondrial protein synthesis was increased with high-fat diet and may contribute to remodeling of the mitochondria to increase lipid oxidation capacity. Mitochondrial adaptations with high-fat diet appear driven by nutrient availability, not intrinsic defects that contribute to insulin resistance.