guanosine-triphosphate and Cachexia

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.

Topics: Adenylyl Cyclases; Adipocytes; Adrenergic beta-Agonists; Animals; Body Composition; Cachexia; Cells, Cultured; Cyclic AMP; Digestive System Neoplasms; Drinking; Eating; Female; Glycoproteins; Guanosine Triphosphate; Humans; Isoproterenol; Lipid Mobilization; Lipolysis; Male; Mice; Mice, Inbred Strains; Mice, Obese; Omentum; Ovarian Neoplasms; Peptides; Seminal Plasma Proteins; Zn-Alpha-2-Glycoprotein

Mice transplanted with a cachexia-inducing colonic adenocarcinoma (MAC16) show a progressive decrease in liver glycogen in direct proportion to the loss of body weight. Such tumours elaborate a lipid mobilizing factor (LMF), which produces a dose-dependent stimulation, not only of adipocyte adenylate cyclase, but also of hepatocyte adenylate cyclase in a GTP-dependent manner. These results suggest that LMF has the capacity to initiate hepatic glycogenolysis through an increase in cyclic AMP.

Topics: Adenocarcinoma; Adenylyl Cyclases; Adipocytes; Adipose Tissue; Animals; Cachexia; Cell Membrane; Cells, Cultured; Colonic Neoplasms; Epididymis; Guanosine Triphosphate; Kinetics; Lipid Mobilization; Liver; Liver Glycogen; Male; Mice; Mice, Inbred Strains; Peptides; Weight Loss