Xanthones from mangosteen prevent lipopolysaccharide-mediated inflammation and insulin resistance in primary cultures of human adipocytes

The xanthones, [alpha]- and [gamma]-mangostin (MG), are major bioactive compounds found in mangosteen and are reported to have antiinflammatory properties in several murine models. Given the association between obesity, chronic low-grade inflammation, and insulin resistance, we examined the effects of [alpha]- and [gamma]-MG on markers of inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes treated with lipopolysaccharide (LPS). [alpha]-and [gamma]-MG decreased the induction by LPS of inflammatory genes, including tumor necrosis factor-[alpha], interleukin (IL)-1[beta], IL-6, IL-8, monocyte chemoattractant protein-1, and Toll-like receptor-2. Moreover, [alpha]-and [gamma]-MG attenuated LPS activation of the mitogen-activated protein kinases (MAPK) c-jun N[H.sub.2]-terminal kinase, extracellular signal-related kinase, and p38. [alpha]-and [gamma]-MG also attenuated LPS activation of c-Jun and activator protein (AP)-1 activity. [gamma]-MG was more effective than [alpha]-MG on an equimolar basis. Furthermore, [gamma]-MG but not [alpha]-MG attenuated LPS-mediated I[kappa]B-[alpha] degradation and nuclear factor-[kappa]B (NF-[kappa]B) activity. In addition, [gamma]-MG prevented the suppression by LPS of insulin-stimulated glucose uptake and PPAR- [gamma], and adiponectin gene expression. Taken together, these data demonstrate that MG attenuates LPS-mediated inflammation and insulin resistance in human adipocytes, possibly by inhibiting the activation of MAPK, NF-[kappa]B, and AP-1.