We have previously shown human lipid-mobilizing factor (LMF) to be homologous with the plasma protein Zn-alpha2-glycoprotein in amino acid sequence, electrophoretic mobility, and immunoreactivity. In this study, both LMF and Zn-alpha2-glycoprotein have been shown to stimulate glycerol release from isolated murine epididymal adipocytes with a comparable dose-response profile. Both LMF and Zn-alpha2-glycoprotein caused a stimulation of adenylate cyclase in murine adipocyte plasma membranes in a GTP-dependent process, with maximum stimulation at 0.1 microM GTP and with saturation at protein concentrations of >5 microg/assay. Administration of LMF to exbreeder male mice over a 89-h period produced a decrease in body weight without a change in food and water intake. Body composition analysis showed a 42% reduction in carcass lipid when compared with controls. Treatment of ob/ob mice with human LMF over a 160-h period also produced a decrease in body weight, with a 19% reduction in carcass fat, without a change in body water or nonfat mass. Serum levels of glycerol and 3-hydroxybutyrate were significantly increased, as was oxygen uptake by interscapular brown adipose tissue, providing evidence of increased lipid mobilization and utilization. Human white adipocytes responded to both LMF and isoprenaline to the same extent, although the maximal response was lower than that for murine white adipocytes. These results suggest that LMF not only has the capacity to induce lipid mobilization and catabolism in mice, but it also has the potential to exert similar effects in cachectic cancer patients.