Short-term and long-term ketogenic diet therapy and the addition of exercise have differential impacts on metabolic gene expression in the mouse energy-consuming organs heart and skeletal muscle

Although a ketogenic diet (KD) is used to treat various metabolic diseases, the organ-specific metabolic changes that occur in response to a KD remain unclear. Therefore, we tested the hypothesis that duration of KD consumption and regular exercise in addition to KD consumption affect metabolic fuel selection at gene levels in heart and skeletal muscle. Six-week-old male C57BL/6J mice were divided into 2 groups, one fed a standard diet and the other fed a KD, and maintained for either 4 weeks (short term) or 12 weeks (long term). The long-term group was further divided into 2 subgroups, and mice in 1 of the 2 groups had an exercise load 5 days a week. Body weight decreased significantly in the KD groups during the first few weeks only. Plasma ketone levels rose and muscle glycogen levels declined significantly in the KD groups, but these changes were less severe in the KD plus exercise group. KD consumption decreased the expression of genes related to glucose utilization in heart and skeletal muscle; however, this decrease did not occur with KD consumption plus exercise. Long-term but not short-term KD consumption increased the expression of genes related to lipid utilization, regardless of exercise. In the KD groups, the expression of genes related to ketolysis was suppressed, and that of genes related to ketogenesis was increased. These results indicate that KD exposure and pairing a KD with exercise have differential impacts on energy substrate selection at gene expression levels in energy-consuming organs, the heart and skeletal muscle.