Adipose tissue IL-6 expression is increased in obesity and is a strong predictor of abnormalities in adipocyte and systemic metabolism. We used adipose tissue organ culture to test the direct effects of IL-6 on leptin expression, lipolysis, and lipoprotein lipase activity. To assess possible interactions with the hormonal milieu, IL-6 effects were tested in the presence or absence of insulin and/or glucocorticoid [dexamethasone (dex)]. Because omental (Om) and abdominal sc depots differ in IL-6 expression, their responses to exogenous IL-6 were compared. Although IL-6 had no significant effects under basal conditions, culture with the combination of IL-6 and dex, compared with dex alone, for 2 d increased leptin in both depots [+95 +/- 30% (sc) and +67 +/- 19% (Om), P < 0.01]; IL-6 did not affect leptin production when added in the presence of insulin. Culture with IL-6 in the absence of hormones moderately increased lipolysis during culture in both sc and Om [+79 +/- 23% (sc) and +26 +/- 9% (Om), each P < 0.01]. IL-6 markedly reduced the high levels of lipoprotein lipase activity in tissue cultured with insulin plus dex. We conclude that high local concentrations of IL-6 can modulate leptin production and lipid metabolism in human adipose tissue.