Injury and inflammation causes severe neurological dysfunction that can be partially reversed by spontaneous regeneration of neuronal network in the central nervous system (CNS). Although CNS environment contains the molecules that inhibit axon regeneration, recent researches pointed out that CNS neuronal network can regenerate spontaneously in the animals of some disease models. Because the CNS environment is separated by the peripheral milieu in the presence of the blood-brain barrier, CNS regeneration is thought to be controlled by the CNS microenvironment. However, we found that factors derived from peripheral tissue leak into the CNS after injury and promote remyelination in a murine model of toxin-induced demyelination. We identified that the remyelination is stimulated by the molecules which are expressed by the peripheral tissues, such as pancreas, adipose disuse, skeletal muscle, and heart. Especially, pancreas-derived FGF21 derived proliferation of oligodendrocyte precursor cells (OPCs) through interactions with beta-klotho, an essential coreceptor of FGF21, and promoted remyelination. In this presentation, I would like to show our recent reports that indicate a potentially important role for the peripheral milieu in promoting CNS regeneration.