An inhibitory effect of resveratrol in the mitotic clonal expansion and insulin signaling pathway in the early phase of adipogenesis

Resveratrol is known as a potent antiobesity compound that acts partly through inhibition of adipogenesis. However, the direct targets responsible for its antiadipogenic action are unclear. Our hypothesis is that resveratrol inhibits adipogenesis through modulation of mitotic clonal expansion (MCE) and cell signaling pathways in the early phase of differentiation. To test this, we examined the effects of resveratrol on MCE and insulin signaling pathway in the early phase of adipogenesis in murine preadipocytes. We observed that the antiadipogenic action of resveratrol is largely limited to the early phase of adipogenesis. Specifically, the presence of resveratrol in the first 24 hours of adipogenesis was required for its antiadipogenic effect. During the first 24 hours of adipogenesis, resveratrol impaired the progression of MCE by suppressing the cell cycle entry of preadipocytes to G2/M phase, and expression of cell cycle regulators cyclin A and cyclin-dependent kinase 2. Concomitantly, resveratrol inhibited insulin signaling pathway in the early phase of adipogenesis. Furthermore, we revealed an inhibitory effect of resveratrol on insulin receptor (IR) activity, and this is likely through a direct physical interaction between resveratrol and IR. The antiadipogenic effect of resveratrol is through inhibition of the MCE and IR-dependent insulin signaling pathway in the early phase of adipogenesis.