Fasting-induced metabolic disease of all inherited deficiencies of the acyl-CoA dehydrogenases is characterized by hypoglycemia, hypoketonemia, and organic aciduria. Mice with these enzyme deficiencies are cold intolerant. To evaluate the potential role that dietary fatty acid chain-length has on a patient's ability to compensate during a metabolic challenge, we fed long-chain acyl CoA dehydrogenase (LCAD) deficient and short-chain acyl CoA dehydrogenase (SCAD) deficient mice a diet rich in medium-chain triglycerides (MCT) or long-chain triglycerides (LCT). To elucidate the importance of maintaining adequate serum glucose concentrations on compensation mechanisms during metabolic challenge, we treated LCAD-/- mice with a solution of 12.5% glucose or saline prior to fasting and a cold-challenge. We found that feeding SCAD deficient mice the LCT diet from weaning increased survival from 40 to 94% during metabolic challenge of cold tolerance. In contrast, there was no benefit to feeding the MCT diet at weaning to LCAD-/- mice; however, there was significant benefit when LCAD-/- mice were fed the MCT diet from the beginning of gestation. Survival during cold-challenge increased from 50 to 93%. In the LCAD-/- mice treated with glucose, despite maintaining serum glucose concentrations at normal or higher concentrations, the LCAD-/- mice were still unable to compensate during metabolic challenge. These results indicate the important influences dietary fatty acids may have by providing enhanced metabolic tolerance in patients with inborn errors of fatty acid oxidation. Furthermore, these studies demonstrate that there may be crucial variables involved in the treatment of these patients, including the patient's specific enzyme deficiency, the quantity and chain-length of dietary fat, which may provide positive effects, as well as the time in development when it was administered. © 2004 Elsevier Inc. All rights reserved.