A MACROPHAGE ENDOGENOUS FACTOR THAT SUPPRESSES ANABOLISM

我们的目标是追踪和调查 引发感染的生化后遗症 一种临床 患有慢性感染或肿瘤的动物的标志是存在 分解代谢状态，可导致恶病质、休克和死亡。 的 这种现象的生物化学基础尚不清楚，但据推测， 触发是一种普遍的性质。 为了深入了解 为了研究这一过程的机制，我们选择了内毒素血症作为模型系统 并将组织培养技术应用于其研究。 来自暴露于以下物质的培养小鼠腹腔巨噬细胞的条件培养基 内毒素被用作介体的来源， 培养的、分化的3 T3-L1细胞显著抑制了 脂蛋白脂肪酶、脂肪酸合成酶和乙酰辅酶A羧化酶。 这 影响，至少部分地，由于对它们的特定影响而出现 合成. 我们的目标是描述 介质与细胞相互作用并调节代谢。 我们计划 通过检查中介对关键监管的影响来实现这一点。 事件包括：胰岛素刺激的核糖体磷酸化， 和细胞蛋白质，磷酸化的细胞蛋白质一般，DNA 甲基化，细胞激素反应和关键的化学修饰 调节酶 使用纯化的介体，我们计划表征 它与细胞相互作用的机制，通过测试特定的 受体。 除了脂肪组织，我们怀疑介体可能 还调节肝脏代谢。 为此，我们将描述 介质对培养的肝细胞的作用，特别是观察其 对脂肪生成和脂肪生成的影响。 介体构成了细胞间通讯系统的一部分 免疫系统和身体的能量储存组织。 在 在对感染的反应中，介体警告能量储存组织， 需要能源来抵抗入侵。 靶细胞的反应是 从存储模式切换到供应模式。 如果入侵时间短， 动物可以迅速恢复和补充商店，但是，如果 侵袭是慢性的，完全消耗导致恶病质， 死亡可能导致。 这些研究具有临床、诊断和药理学相关性， 代表了理解和改善 传染病的代谢后遗症

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.