1,3,6,7-Tetrahydroxy-8-prenylxanthone ameliorates inflammatory responses resulting from the paracrine interaction of adipocytes and macrophages

Abstract

Background and Purpose: Chronic inflammation in adipose tissue is critical in the onset and development of insulin resistance and type 2 diabetes. Macrophage infiltration into adipose tissue and pro-inflammatory polarization play key roles in adipose tissue inflammation. The fruit hull of mangosteen (Garcinia mangostana) is used in traditional medicine to treat various inflammatory diseases. However, its role in regulating adipose tissue inflammation is unexplored. This study was designed to identify xanthones from G. mangostana, which could ameliorate adipose tissue inflammation. Experimental Approach: Expressions of inducible NOS, cytokines, chemokines and components of the NF-κB and MAPKs pathways were evaluated using Western blotting, immunofluorescence, quantitative real-time PCR or ELISA. The migration of macrophages towards adipocytes was tested using Transwell experiments in vitro. A murine model of LPS-induced acute inflammation was used to examine effects of 1,3,6,7-tetrahydroxy-8-prenylxanthone (TPX) on inflammatory responses in adipose tissue in vivo. Key Results: From a series of xanthones isolated from G. mangostana, TPX was identified as a potent inhibitor of LPS-induced NO production and IL-6 secretion in RAW264.7 macrophages. TPX ameliorated LPS-induced inflammatory responses in RAW264.7 macrophages, and TNF-α-mediated inflammation in 3T3-L1 adipocytes, through inhibiting MAPKs and NF-κB activation and promoting sirtuin 3 expression. TPX also blocked RAW264.7 macrophages migration towards 3T3-L1 adipocytes in co-cultures. Furthermore, TPX alleviated LPS-induced adipose tissue inflammation in vivo by reducing pro-inflammatory cytokines and preventing the pro-inflammatory polarization of macrophages. Conclusions and Implications: Taken together, our results indicate that TPX disrupts the inflammatory responses between macrophages and adipocytes, and attenuates adipose tissue inflammation.