ACUTE METABOLIC EFFECTS OF HUMAN RECOMBINANT TUMOR NECROSIS FACTOR-BETA IN THE RAT

Background: Cancer cachexia is associated with several alterations in host metabolism, including hypoaminoacidemia and an increase in glucon eogenesis (GLC) and lipolysis. Tumor necrosis factor beta (TNFbeta), a lymphokine released by mitogen-activated T lymphocytes and several ca ncer cell lines, causes an increase in lipolysis in 3T3L1 adipocytes. Since little is known about the metabolic effects of TNFbeta in vivo, we examined its acute effects in the rat. Methods: Twenty-eight male F ischer rats were injected intraperitoneally with TNFbeta (250 mug/kg) or saline (CTL), and after 4 h, isolated hepatocytes were obtained (by in situ collagenase liver perfusion [n = 12]) or aortic blood was col lected (n = 16). Hepatocytes were incubated with 10 mM alanine (ALA) o r 10 mM lactate (LAC), and glucose production was measured. Rates of G LC (nmol glucose/10(6) cells/min) were determined by linear regression . Plasma lactate, glucose, insulin, and amino acids (AA) (nmol/ml) wer e measured, and values were expressed as means +/- SEM. Comparisons be tween groups were made by unpaired t test or Mann-Whitney U test, and significance was defined as p < 0.05. Results: TNFbeta caused a 130% i ncrease in gluconeogenesis from alanine (2.7 0.5 vs 1.2 +/- 0.2 nmol g lucose/10(6) cells/min, TNF vs CTL), and a 60% increase from lactate ( 7.5 +/- 1.0 vs 4.6 +/- 0.5 nmol glucose/10(6) cells/min, TNF vs CTL). Plasma insulin levels in TNF treated rats were 1.2 +/- 0.2 ng/ml compa red to 1.1 +/- 0.2 ng/ml in CTL. Total amino acid levels in TNF treate d rats were 3,175 111 nmol/ml compared to 3,190 +/- 103 nmol/ml in CTL . Conclusion: In vivo TNFbeta causes an increase in hepatic gluconeoge nesis from alanine and lactate with no change in plasma insulin or ami no acids.