Inhibition of visfatin alleviates sepsis-induced intestinal damage by inhibiting Hippo signaling pathway.

BACKGROUND: The aim of this study is to investigate role of Visfatin, one of the pro-inflammatory adipokines, in sepsis-induced intestinal injury and to clarify the potential mechanism. METHODS: C57BL/6 mice underwent cecal ligation and puncture (CLP) surgery to establish sepsis model in vivo. Intestinal epithelial cells were stimulated with LPS to mimic sepsis-induced intestinal injury in vitro. FK866 (the inhibitor of Visfatin) with or without XMU-MP-1 (the inhibitor of Hippo signaling) was applied for treatment. The expression levels of Visfatin, NF-κB and Hippo signaling pathways-related proteins were detected by western blot or immunohistochemistry. The intestinal cell apoptosis and intestinal injury were investigated by TUNEL staining and H&E staining, respectively. ELISA was used to determine the production of inflammatory cytokines. RESULTS: The expression of Visfatin increased in CLP mice. FK866 reduced intestinal pathological injury, inflammatory cytokines production, and intestinal cell apoptosis in sepsis mice. Meanwhile, FK866 affected NF-κB and Hippo signaling pathways. Additionally, the effects of FK866 on inflammatory response, apoptosis, Hippo signaling and NF-κB signaling were partly abolished by XMU-MP-1, the inhibitor of Hippo signaling. In vitro experiments also revealed that FK866 exhibited a protective role against LPS-induced inflammatory response and apoptosis in intestinal cells, as well as regulating NF-κB and Hippo signaling, whereas addition of XMU-MP-1 weakened the protective effects of FK866. CONCLUSION: In short, this study demonstrated that inhibition of Visfatin might alleviate sepsis-induced intestinal injury through Hippo signaling pathway, supporting a further research on Visfatin as a therapeutic target.

Nesfatin-1 acts on the dopaminergic reward pathway to inhibit food intake.

Nesfatin-1 is a novel 82-amino acid anorectic peptide. Previous studies of nesfatin-1 have focused on hypothalamic and brainstem circuits implicated in feeding regulation. Recently, nesfatin-1 expression was also reported in the nucleus accumbens (NAc), amygdaloid nucleus and insular cortex of mice, areas that are related to the control of reward behavior. Therefore, it is possible that nesfatin-1 might also inhibit food intake via central reward circuits. Using electrophysiology and electrochemical and behavioral tests, we investigated the effect of nesfatin-1 on the dopaminergic reward pathway between the ventral tegmental area (VTA) and the NAc. Our results showed that injection of nesfatin-1 into the VTA significantly inhibited dark-phase cumulative food intake in mice. The excitability of VTA dopaminergic neurons was inhibited by nesfatin-1. In addition, nesfatin-1 decreased dopamine release in the NAc. Therefore, we concluded that nesfatin-1 acts on dopaminergic neurons, and these effects might contribute to the decrease of food intake that results from the injection of nesfatin-1 into the VTA.