Skeletal muscle and fat tissue are involved in the homeostasis of glucose metabolism. Here, we introduce new bioactive factors derived from skeletal muscle and fat tissue. Musclin was identified via signal sequence trap of mouse skeletal muscle cDNAs. Musclin protein contained a region homologous to nariuretic peptide family. Its mRNA was expressed almost exclusively in skeletal muscle of mice, and regulated by nutritional changes. Recombinant musclin protein significantly attenuated insulin-stimulated glucose uptake and glycogen synthesis in myocytes. A newly identified adipocytokine, visfatin, is highly enriched in the visceral fat of both human and mice and whose expression level in plasma increases during the development of obesity. Visfatin exerted insulin- mimetic effects in cultured cells and lowered plasma glucose levels in mice. Heterozygous knockout mice of visfatin had modestly higher levels of plasma glucose relative to wild type littermates. Surprisingly, visfatin binds to and activates the insulin receptor. Production of ROS increased selectively in fat tissue of obese mice. In cultured fat cells, oxidative stress caused dysregulated production of adipocytokines, including adiponectin, PAI-1, IL-6, and MCP-1. In obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in fat tissue, attenuated the dysregulation of adipocytokines, and improved diabetes. Further study on the physiological role of these factors may lead to new insights into glucose homeostasis. [J Physiol Sci. 2006;56 Suppl:S28]