The β-catenin-dependent Wnt signaling plays a role in adipogenesis, myogenesis, and glucose homeostasis.The aim of this study was to assess adipose tissue and skeletal muscle expression of Wnt/β-catenin signaling genes in a young healthy population according to insulin sensitivity and its regulation by hyperinsulinemia and free fatty acids.We examined 117 male volunteers. The participants were divided into subgroups of high-insulin sensitivity (IS) and low-IS on the basis of a 2-hour euglycemic clamp. In 20 subjects, the clamp was prolonged to 6 hours. After 1 week, another 6-hour clamp, with Intralipid/heparin infusion, was performed. Tissue biopsies were performed before each clamp and after 6-hour clamps. Additionally, we collected muscle biopsies from another group of 16 male subjects for cell cultures. Myotubes were treated with insulin separately and in combination with palmitate.We found decreased adipose tissue WNT10B, FZD1/8, LRP5, DVL2, CTNN1B, TCF7L2, and AXIN2 and increased muscle WNT10B, FZD1/8, LRP6, DVL1, GSK3B, CTNNB1, TCF7L2, AXIN2, MYC, and CCND1 expression in the low-IS group. Hyperinsulinemia resulted in a decrease in adipose tissue FZD4, LRP5/6, TCF7L2, and AXIN2 and an increase in muscle FZD1/8, DVL1/2/3, TCF7L2, AXIN2, and MYC expression. These changes disappeared after free fatty acid elevation. In myotubes, insulin increased the expression of FZD1, DVL2, CTNNB1, and TCF7L2, whereas palmitate abolished these effects.The association of β-catenin-dependent Wnt signaling with insulin resistance is tissue specific. Observed changes might reflect a compensatory mechanism to increase muscle glucose uptake and to generate new fat cells in insulin-resistant conditions.