Infiltration of monocyte-derived macrophages into adipose tissue may contribute to tissue and systemic inflammation and insulin resistance. We hypothesized that pioglitazone (Pio) could specifically reduce the inflammatory response of adipocytes to factors released by monocytes/macrophages. We show that macrophage factors (Mphi-factors) greatly increase expression levels of proinflammatory adipokines, chemokines, and adhesion molecules in human subcutaneous and visceral adipose tissue (SAT and VAT) as well as in adipocytes (up to several hundredfold of control). Compared with SAT, VAT showed enhanced basal and Mphi-factor-induced inflammatory responses. Mphi-factors also induced greater lipolysis in adipocytes, as assessed by concentrations of glycerol released from the cells (196 +/- 13 vs. 56 +/- 7 microM in control, P < 0.05). Pretreatment of adipose tissue or adipocytes with Pio reduced these responses to Mphi-factors (by 13-86%, P < 0.05) and prevented Mphi-factor suppression of adiponectin expression. Furthermore, Pio pretreatment of adipocytes and macrophages tended to further reduce inflammatory responses of adipocytes to Mphi-factors and monocyte adhesion to Mphi-factor-activated adipocytes. In support of these in vitro data, media conditioned by monocytes isolated from impaired glucose-tolerant subjects treated with Pio (compared with placebo) induced release of lower concentrations of proinflammatory adipokines and glycerol (100 +/- 7 vs. 150 +/- 15 microM, P < 0.05) from adipocytes. In summary, Pio decreases inflammatory responses in adipose tissue/cells induced by monocytes/macrophages by acting on either or both cell types. These beneficial effects of Pio may attenuate proinflammatory responses resulting from monocyte/macrophage infiltration into adipose tissue and suppress tissue inflammation resulting from the interaction between both cell types.