Loss of adipose tissue in cancer cachexia in mice bearing the MAC16 tumour arises from an increased lipid mobilisation through increased expression of zinc-alpha2-glycoprotein (ZAG) in white (WAT) and brown (BAT) adipose tissue. Glucocorticoids have been suggested to increase ZAG expression, and this study examines their role in cachexia and the mechanisms involved. In mice bearing the MAC16 tumour, serum cortisol concentrations increased in parallel with weight loss, and the glucocorticoid receptor antagonist RU38486 (25 mg kg(-1)) attenuated both the loss of body weight and ZAG expression in WAT. Dexamethasone (66 microg kg(-1)) administration to normal mice produced a six-fold increase in ZAG expression in both WAT and BAT, which was also attenuated by RU38486. In vitro studies using 3T3-L1 adipocytes showed dexamethasone (1.68 microM) to stimulate lipolysis and increase ZAG expression, and both were attenuated by RU38486 (10 microM), anti-ZAG antibody (1 microg ml(-1)), and the beta3-adrenoreceptor (beta3-AR) antagonist SR59230A (10 microM). Zinc-alpha2-glycoprotein also increased its own expression and this was attenuated by SR59230A, suggesting that it was mediated through the beta3-AR. This suggests that glucocorticoids stimulate lipolysis through an increase in ZAG expression, and that they are responsible for the increase in ZAG expression seen in adipose tissue of cachectic mice.