Early Skeletal Muscle Adaptations to Short-Term High-Fat Diet in Humans Before Changes in Insulin Sensitivity

ObjectiveThe purpose of this investigation was to understand the metabolic adaptations to a short-term (5 days), isocaloric, high-fat diet (HFD) in healthy, young males. MethodsTwo studies were undertaken with 12 subjects. Study 1 investigated the effect of the HFD on skeletal muscle substrate metabolism and insulin sensitivity. Study 2 assessed the metabolic and transcriptional responses in skeletal muscle to the transition from a fasted to fed state using a high-fat meal challenge before and after 5 days of the HFD. ResultsStudy 1 showed no effect of a HFD on skeletal muscle metabolism or insulin sensitivity in fasting samples. Study 2 showed that a HFD elicits significant increases in fasting serum endotoxin and disrupts the normal postprandial excursions of serum endotoxin, as well as metabolic and transcriptional responses in skeletal muscle. These effects after 5 days of the HFD were accompanied by an altered fasting and postprandial response in the ratio of phosphorylated- to total-p38 protein. These changes all occurred in the absence of alterations in insulin sensitivity. ConclusionsOur findings provide evidence for early biological adaptations to high-fat feeding that proceed and possibly lead to insulin resistance.