Lammers G, Poelkens F, van Duijnhoven NT, Pardoel EM, Hoenderop JG, Thijssen DH, Hopman MT. Expression of genes involved in fatty acid transport and insulin signaling is altered by physical inactivity and exercise training in human skeletal muscle. Am J Physiol Endocrinol Metab 303: E1245-E1251, 2012. First published October 9, 2012; doi:10.1152/ajpendo.00356.2012.-Physical deconditioning is associated with the development of chronic diseases, including type 2 diabetes and cardiovascular disease. Exercise training effectively counteracts these developments, but the underlying mechanisms are largely unknown. To gain more insight into these mechanisms, muscular gene expression levels were assessed after physical deconditioning and after exercise training of the lower limbs in humans by use of gene expression microarrays. To exclude systemic effects, we used human models for local physical inactivity (3 wk of unilateral limb suspension) and for local exercise training (6 wk of functional electrical stimulation exercise of the extremely deconditioned legs of individuals with a spinal cord injury). The most interesting subset of genes, those downregulated after deconditioning as well as upregulated after exercise training, contained 18 genes related to both the "insulin action" and "adipocytokine signaling" pathway. Of these genes, the three with strongest up/downregulation were the muscular fatty acid-binding protein-3 (FABP3), the fatty acid oxidizing enzyme hydroxyacyl-CoA dehydrogenase (HADH), and the mitochondrial fatty acid transporter solute carrier 25 family member A20 (SLC25A20). The expression levels of these genes were confirmed using RT-qPCR. The results of the present study indicate an important role for a decreased transport and metabolism of fatty acids, which provides a link between physical activity levels and insulin signaling.transcriptome; microarray; fatty acid metabolism; insulin resistance THE HUMAN GENOME HAS EVOLVED on the basis of a physically active lifestyle, but our society has become increasingly sedentary. Physical inactivity has detrimental health consequences, including the development of insulin resistance and eventually type 2 diabetes and cardiovascular disease (8, 41). Recently, it has been demonstrated that even a 2-wk reduction in daily activity level can be sufficient to increase insulin resistance in healthy subjects, as does 9 days of strict bed rest (1, 26). On the other end of the spectrum, a single bout of exercise can reduce insulin resistance (17), regular physical activity reduces the risk of developing diabetes (21, 29), and significant exercise effects have been reported in diabetics (9), making exercise a powerful tool in the prevention and management of type 2 diabetes.Skeletal muscle accounts for the majority of insulin-induced glucose uptake. Binding of insulin to its receptor on the cellular plasma membrane leads, via the activation of intracellular insulin receptor substrates 1 and 2 (IRS1/2), to translocation of the GLUT4 glucose transporter to the plasma membr...