Blockade of visfatin induction by oleanolic acid via disturbing IL-6-TRAF6-NF-κB signaling of adipocytes

Oleanolic acid is a pentacyclic triterpenoid naturally present in foods and medicinal plants with anticancer, antioxidant, and antiaging properties. The current study elucidated that oleanolic acid inhibited the production of insulin-mimetic and inflammatory adipokine of visfatin during adipogenic differentiation of 3T3-L1 adipocytes. Adipocytes were cultured in an adipogenic media with and without 1-25 mu M oleanolic acid up to 8 days for differentiation. The cellular expression and secretion of visfatin was markedly enhanced in differentiating adipocytes, which was dose-dependently attenuated by 1-25 mu M oleanolic acid. Secretion of interleukin (IL)-6 and macrophage inflammatory protein (MIP)-2 was highly elevated during differentiation, which was much earlier than visfatin production of adipocytes. The visfatin production was secondary to inflammatory IL-6 and MIP-2. This study further elucidated that nuclear factor-kappa B (NF-kappa B) signaling was responsible for cellular production of visfatin. NF-kappa B was activated by translocating into the nucleus with increased phosphorylation of inhibitory kappa B (I kappa B), which was disturbed by oleanolic acid. Cellular expression of tumor necrosis factor receptor associated factor 6 (TRAF6), a NF-kappa B upstream, was upregulated in parallel with transactivation with NF-kappa B. The TRAF6 induction required the auto-stimulation of inflammatory IL-6 and MIP-2. These results demonstrate that oleanolic acid inhibited visfatin and its inflammatory response during adipocyte differentiation through blocking IL-6-TRAF6-NF-kappa B signaling. Therefore, oleanolic acid may be a potent therapeutic agent targeting against adipogenesis and visfatin-linked inflammation.