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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA015813-11
Application #
3164285
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1979-02-01
Project End
1989-02-28
Budget Start
1988-07-01
Budget End
1989-02-28
Support Year
11
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Kannan, R; Gan-Elepano, M; Baker, N (1992) Anorexic contribution to increased linoleate mobilization and oxidation in lymphoma-bearing mice. Lipids 27:117-23
Lin, C; Blank, W; Ceriani, R L et al. (1992) Effect of human mammary MX-1 tumor on plasma free fatty acids in fasted and fasted-refed nude mice. Lipids 27:33-7
Lin, C; Blank, E W; Ceriani, R L et al. (1991) Evidence of extensive phospholipid fatty acid methylation during the assumed selective methylation of plasma free fatty acids by diazomethane. Lipids 26:548-52
Barrett, P H; Baker, N; Nestel, P J (1991) Model development to describe the heterogeneous kinetics of apolipoprotein B and triglyceride in hypertriglyceridemic subjects. J Lipid Res 32:743-62
Kannan, R; Gan-Elepano, M; Baker, N (1990) Reduced suppression of plasma saturated fatty acid mobilization and oxidation by feeding in lymphoma-bearing mice. Cancer Res 50:2221-7
Baker, N; Gan-Elepano, M; Guthrie, B A et al. (1989) Turnover and fate of plasma free fatty acids in briefly-fasted lymphoma-bearing mice. Lipids 24:1028-34
Lyon, I; Ookhtens, M; Montisano, D et al. (1988) Fat pad triacylglycerol fatty acid loss and oxidation as indices of total body triacylglycerol fatty acid mobilization and oxidation in starving mice. Biochim Biophys Acta 958:188-98
Baker, N; Gan-Elepano, M; Guthrie, B A et al. (1987) Delayed recycling of plasma FFA in mice: revised model of turnover and oxidation. Am J Physiol 253:R746-55
Ookhtens, M; Montisano, D; Lyon, I et al. (1987) Transport and metabolism of extracellular free fatty acids in adipose tissue of fed and fasted mice. J Lipid Res 28:528-39
Ookhtens, M; Montisano, D; Lyon, I et al. (1986) Inhibition of fatty acid incorporation into adipose tissue triglycerides in Ehrlich ascites tumor-bearing mice. Cancer Res 46:633-8

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