The xanthones, α- and γ-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 α- and γ-MG on markers of inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes treated with lipopolysaccharide (LPS). α- and γ-MG decreased the induction by LPS of inflammatory genes, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, monocyte chemoattractant protein-1, and Toll-like receptor-2. Moreover, α- and γ-MG attenuated LPS activation of the mitogen-activated protein kinases (MAPK) c-jun NH2-terminal kinase, extracellular signal-related kinase, and p38. α- and γ-MG also attenuated LPS activation of c-Jun and activator protein (AP)-1 activity. γ-MG was more effective than α-MG on an equimolar basis. Furthermore, γ-MG but not α-MG attenuated LPS-mediated IκB-α degradation and nuclear factor-κB (NFkB) activity. In addition, γ-MG prevented the suppression by LPS of insulin-stimulated glucose uptake and PPAR-γ 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-κB, and AP-1. J. Nutr. 139: 1185–1191, 2009.