A potential effector of the protein-sparing adaptation to fasting could be the increased availability of endogenous long-chain fatty acids. Were this hypothesis correct, infusion of medium-chain triglycerides to increase the plasma concentration of medium-chain fatty acids might also result in protein sparing. However, in most in vitro studies in rat muscle, octanoate increases the oxidation of the essential amino acid leucine. Therefore leucine metabolism was assessed with infusions of [3H]leucine and a-[14C]ketoisocaproate ([14C]KIC) before and during an infusion of trioctanoin in conscious dogs. Plasma octanoate increased from less than 30 to 528 microM over the 3 h of infusion. Plasma leucine and KIC concentrations decreased by 65-70% (P less than 0.01) over the first 2 h of infusion. Leucine oxidation, estimated from the expired 14CO2 and the plasma [14C]KIC specific activity, as well as from an open two-pool model, decreased. By use of these isotope models, the rates of leucine coming from and going to protein decreased (P less than 0.05 to P less than 0.01). Interconversion of leucine and KIC estimated from the open two-pool model decreased by 80% (P less than 0.01). These changes were accompanied by a 36% decrease in the plasma concentration of total plasma amino acids. Within the confines of the isotope models employed, these data are consistent with the hypothesis that increased fatty acid oxidation decreases protein turnover and may spare essential amino acids.