It is our objective to pursue and investigation of the molecualr events that trigger the biochemical sequelae of infection. One of the clinical hallmarks of animals with chronic infections or tumors is the presence of a catabolic state which can proceed to cachexia, shock, and death. The biochemical basis for this phenomenon is not understood but presumably once triggered is of a universal nature. In order to gain insight into the mechanism of this process, we have selected endotoxemia as a model system and have applied tissue culture techniques to its investigation. Conditioned medium from cultured mouse peritoneal macrophages exposed to endotoxin is utilized as a source of a mediator that when added to cultured, differentiating 3T3-L1 cells markedly suppresses the activity of lipoprotein lipase, fatty acid synthetase and acetyl CoA carboxylase. This effect, at least in part, appears due to a specific effect on their synthesis. It is our objective to characterize the mechanism by which the mediator interacts with cells and regulates metabolism. We plan to accomplish this by examining the effect of the mediator on key regulatory events including; insulin stimulatable phosphorylation of both ribosomal and cellular protein, phosphorylation of cellular protein in general, DNA methylation, cellular hormonal response and chemical modification of key regulatory enzymes. Using purified mediator, we plan to characterize the mechanism by which it interacts with the cell by testing for specific receptors. In addition to adipose tissue, we suspect that the mediator may also regulate hepatic metabolism. To that end we will characterize the effect of the mediator on cultured hepatocytes specifically looking at its effect on lipogenesis and gluconeogenesis. The mediator constitutes part of a communication system between the cells of the immune system and the energy storage tissues of the body. In response to infection, the mediator warns energy storage tissues of the need for energy to combat the invasion. The target cells respond by switching from a storage to a supply mode. If the invasion is short, the animal can quickly recover and replenish the stores, however, if the invasion is of a chronic nature, complete depletion leading to cachexia and death can result. These studies have clinical, diagnostic and pharmacologic relevance and represent a significant step toward understanding and perhaps ameliorating the metabolic sequelae of infectious diseases.
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