A High-Fat Diet Elicits Differential Responses in Genes Coordinating Oxidative Metabolism in Skeletal Muscle of Lean and Obese Individuals

Context: In lean individuals, increasing dietary lipid can elicit an increase in whole body lipid oxidation; however, with obesity the capacity to respond to changes in substrate availability appears to be compromised. Objective: To determine whether the responses of genes regulating lipid oxidation in skeletal muscle differed between lean and insulin resistant obese humans upon exposure to a high-fat diet (HFD). Design and Setting: A 5-d prospective study conducted in the research unit of an academic center. Participants: Healthy, lean (n = 12; body mass index = 22.1 +/- 0.6 kg/m(2)), and obese (n = 10; body mass index = 39.6 +/- 1.7 kg/m(2)) males and females, between ages 18 and 30. Intervention: Participants were studied before and after a 5-d HFD (65% fat). Main Outcome Measures: Skeletal muscle biopsies (vastus lateralis) were obtained in the fasted and fed states before and after the HFD and mRNA content for genes involved with lipid oxidation determined. Skeletal muscle acylcarnitine content was determined in the fed states before and after the HFD. Results: Peroxisome proliferator activated receptor (PPAR) alpha mRNA content increased in lean, but not obese, subjects after a single high-fat meal. From Pre- to Post-HFD, mRNA content exhibited a body size x HFD interaction, where the lean individuals increased while the obese individuals decreased mRNA content for pyruvate dehydrogenase kinase 4, uncoupling protein 3, PPAR alpha, and PPAR gamma coactivator-1 alpha (P <= 0.05). In the obese subjects medium-chain acylcarnitine species tended to accumulate, whereas no change or a reduction was evident in the lean individuals. Conclusions: These findings indicate a differential response to a lipid stimulus in the skeletal muscle of lean and insulin resistant obese humans. (J Clin Endocrinol Metab 96: 775-781, 2011)