The effects of recombinant tumour necrosis factor (cachectin) on metabolism in isolated rat adipocyte, hepatocyte and muscle preparations.
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ABSTRACT:
SUBMITTER: Rofe AM
PROVIDER: S-EPMC1148481 | biostudies-other | 1987 Nov
REPOSITORIES: biostudies-other
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Project description:The effects of acute administration of tumour necrosis factor-alpha (cachectin) (TNF-alpha) or of malignant tumour growth (Walker-256 carcinosarcoma) on hepatic availability and uptake of individual amino acids were compared. The results show that, in spite of lowering the hepatic availability of alanine, aspartate, serine, glycine and proline, the cytokine increased both the total amino acid hepatic uptake and the individual uptakes of alanine, glutamate, serine, threonine, proline, lysine and arginine, while decreasing those of leucine, isoleucine and phenylalanine. Tumour burden resulted in an increase in the hepatic availability of glutamine, threonine, glycine, lysine, leucine, isoleucine, valine and phenylalanine. Total liver amino acid uptake was unaffected, whereas the individual uptakes of alanine, threonine and proline were increased and those of glutamate, glutamine, serine and leucine were decreased. When effects of the cytokine are compared with those induced by tumour growth, there are similar increases in net utilization for alanine, proline and leucine, and a 3-fold difference in the increase observed for threonine. Unmatched effects are seen for glutamate, glutamine, aspartate, glycine, lysine, arginine, valine, phenylalanine and serine.
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Project description:Bacterial endotoxins cause enhanced protein metabolism in liver, and protein catabolism in muscle and skin. These effects may be mediated by cytokines such as interleukin 1 (IL1) and tumour necrosis factor (TNF). The study investigates the timing and magnitude of effects of recombinant human TNF alpha on protein synthesis and protein and RNA content of the liver, tibialis muscle and skin of Wistar rats. Intravenous doses of 30 and 300 micrograms/kg of body weight were used and effects examined 8 h and 24 h after injection. Muscle protein content and synthetic rate were reduced at 8 h post-injection by over 18% and 20% respectively. Protein synthesis returned to normal after the lowest dose but remained depressed 24 h after the highest dose due to the accompanying anorexia. Opposite effects were observed in liver. Protein fractional synthetic rate (FSR) was increased by over 26% at 8 h post-injection and remained elevated 24 h after the higher but not lower dose of TNF. Total protein and RNA contents were significantly higher than controls at this time. Skin protein synthesis was unaffected by TNF; however an increase in protein and RNA content was observed at 8 h post-injection with the lower dose of TNF. Liver and muscle respond in a similar but more rapid way to TNF than to endotoxin. The response of skin is however totally different. While muscle may contribute amino acids for enhanced hepatic protein synthesis following exposure to TNF, skin does not.
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Project description:We investigated the mechanism by which the endotoxin-induced macrophage secretory protein cachectin is able to suppress the activity of lipoprotein lipase in 3T3-L1 adipocytes. The loss in activity results from an effect on the synthesis of the enzyme, as determined by a decreased incorporation of [35S]methionine into immunoprecipitable lipoprotein lipase. The results were nearly identical whether crude conditioned medium or a highly purified preparation was utilized as a source of cachectin. [35S]Methionine incorporation into acid-precipitable protein was minimally affected by purified cachectin, suggesting that the suppression of the lipoprotein lipase was not due to a general suppression of protein synthesis. These results, taken together with our previous work, provide additional evidence that cachectin and tumour necrosis factor are functionally identical.
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Project description:Tumour necrosis factor (TNF) is an important mediator of endotoxin-induced vascular collapse and other inflammatory reactions. Eicosanoids have been implicated in the pathogeensis of these responses. In order to explore further the potential interactions between TNF and eicosanoid metabolism in eliciting vascular responses, we studied the effects of TNF on the bovine endothelial cell line CPAE. TNF induced cellular retraction observed by light microscope. This morphological change was monitored by the passage of iodinated protein A between adjacent cells and by release of [3H]arachidonic acid metabolites from cells. Both the morphological and functional responses were abrogated by inhibition of eicosanoid synthesis with BW755c. The release of [3H]arachidonic acid metabolites appeared to be mediated by a transient increase in phospholipase A2 activity. Phospholipase C activity was not affected by TNF. The maximal increase in phospholipase A2 activity occurred at 5 min following the addition of TNF. Phospholipase A2 activation, [3H]arachidonic acid-metabolite synthesis and passage of iodinated protein A, required both RNA and protein synthesis and were associated with an increase in the synthesis of a recently described phospholipase A2-activating protein. The Bordetella pertussis toxin, islet-activating protein, also inhibited the increase in phospholipase A2 activity, the release of [3H]arachidonic acid metabolites and the passage of iodinated protein A, suggesting that the TNF receptor-ligand interaction resulting in cellular retraction, phospholipase A2 activation and eicosanoid synthesis, is coupled through the Ni guanine nucleotide regulatory protein in these cells.
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Project description:The effects of acute administration of either tumour necrosis factor-alpha (cachectin) (TNF) or interleukin-1-beta (IL-1), or of tumour growth (Walker-256 carcinosarcoma), on blood amino acid concentrations and tissue alpha-amino[1-14C]isobutyrate (AIB) uptake in virgin and lactating rats were compared. Both monokines decreased the blood concentrations of those amino acids (serine, glycine, alanine and proline) transported via the A system. Tumour growth decreased the blood concentrations of serine, proline and histidine, whereas the concentrations of glutamine and leucine were increased. IL-1 decreased the intestinal absorption of AIB in all groups studied; TNF or tumour growth had no effect. Tissue AIB uptake was increased (1.5-2.5-fold) in liver, whereas it was decreased in heart and skeletal muscle of the three treatment groups (except skeletal muscle of the IL-1-treated rats). Lactating rats had lower hepatic uptake of AIB compared with livers of virgin rats. IL-1 increased the hepatic uptake of AIB in lactating rats, but not to the values seen in virgin rats treated with IL-1; there was no effect of the cytokine on muscle or mammary-gland uptake. In adrenalectomized rats, the stimulatory effect of IL-1 on hepatic AIB uptake was diminished, whereas that of TNF still persisted. IL-1 caused a marked decrease of AIB uptake in muscle and heart of adrenalectomized rats, which was accompanied by an increase in the blood concentrations of branched-chain amino acids. These effects did not occur with TNF. It is concluded that the effects of the cytokines on tissue amino acid metabolism may depend on a differential endocrine response involving glucagon and/or glucocorticoids.
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Project description:Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin sensitivity by promoting hepatic insulin clearance and mediating suppression of fatty acid synthase activity. Feeding C57BL/6J male mice with a high-fat (HF) diet for 3-4 weeks triggered a >60% decrease in hepatic CEACAM1 levels to subsequently impair insulin clearance and cause systemic insulin resistance and hepatic steatosis. This study aimed at investigating whether lipolysis drives reduction in hepatic CEACAM1 and whether this constitutes a key mechanism leading to diet-induced metabolic abnormalities. Blocking lipolysis with a daily intraperitoneal injection of nicotinic acid in the last two days of a 30-day HF feeding regimen demonstrated that white adipose tissue (WAT)-derived fatty acids repressed hepatic CEACAM1-dependent regulation of insulin and lipid metabolism in 3-month-old male C57BL/6J mice. Adenoviral-mediated CEACAM1 redelivery countered the adverse metabolic effect of the HF diet on insulin resistance, hepatic steatosis, visceral obesity, and energy expenditure. It also reversed the effect of HF diet on inflammation and fibrosis in WAT and liver. This assigns a causative role for lipolysis-driven decrease in hepatic CEACAM1 level and its regulation of insulin and lipid metabolism in sustaining systemic insulin resistance, hepatic steatosis, and other abnormalities associated with excessive energy supply.
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