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

Objective—The 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. Methods—Two 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 response in skeletal muscle to the transition from a fasted-to-fed state using a high fat meal challenge prior to and following 5 days of HFD. Results—Study 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, and metabolic and transcriptional responses in skeletal muscle. These effects following 5 days of 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. Conclusions—Our findings provide evidence for early biological adaptations to high fat feeding that proceed and possibly lead to insulin resistance.