Our long-ranged goals are to find ways to regulate fat metabolism by nutritional and hormonal means in cancer-bearing animals so that the host's cachexia is ameliorated. We shall measure rates of mobilization and oxidation of metabolic fuels and their storage and attempt to develop simple, reliable ways to detect abnormal rates under different dietary and hormonal conditions. This project focuses upon two hypothetical causes of cachexia in tumor-bearing mice: 1) tumor cells produce a factor, LMF, that causes an increased rate of FFA mobilization (evidenced by an increased rate of FFA oxidation to CO2) from adipose tissue in tumor-bearing mice; 2) macrophages produce a factor, tumor necrosis factor (TNF) that inhibits the activity of adipose tissue lipoprotein lipase (LPL), thus inhibiting the deposition of fat in tumor-bearing animals. These studies also explore the possiblity that the putative humoral factors are more effective in the fully fed than in briefly fasted states and that essential and non- essential fatty acids may be affected differently by cancer- derived (or macrophage derived) humoral factors. These hypotheses will be tested by measuring rates of FFA mobilization and oxidation and by measuring rates of VLDL-TGFA uptake and deposition by white adipose tissue in vivo during tumor growth and in response to infusions of graded doses of LMF and TNF in tumor-bearing and control mice using tracer techniques. TGFA uptake will be correlated with lipoprotein lipase activity measurements. Parallel studies will also be done in skeletal and heart muscle to test specificity of action with respect to changes in functional LPL activity. the studies will include mildly fasted states (through use of regular and reversed light cycle conditions), and inclusion of pair-fed as well as ad libitum-fed controls. 14C- labeled palmitate and linoleate will be used as the tracers and data will be analyzed by multicompartmental analysis. Particular attention will be given to possible changes in rates of fat metabolism at early stages of tumor growth, during periods of transient hypertriglyceridemia prior to the nearly complete depletion of white adipose tissue TGFA stores in AKR lymphoma- bearing mice.
Showing the most recent 10 out of 11 publications
