Role of Ceramide in Hepatic Insulin Resistance

多肽激素胰岛素刺激葡萄糖和其他物质的吸收和储存 营养物质进入脂肪组织和骨骼肌，同时抑制葡萄糖从肝脏流出。 当正常剂量的激素不能引起这些合成代谢时，就会发生胰岛素抵抗。 这种情况是心血管疾病、2型糖尿病和某些形式的糖尿病的危险因素 癌症。导致胰岛素抵抗的致病因素(如饱和脂肪酸、肿瘤 已经证明)选择性地诱导神经酰胺的合成， 已被证明能拮抗胰岛素作用的鞘磷脂。我们提出的发现表明， 抑制啮齿动物神经酰胺合成改善饱和脂肪引起的胰岛素抵抗， 糖皮质激素和肥胖。此外，我们还包括初步数据，确定肝脏可能是 神经酰胺作用，即白色脂肪细胞分泌神经酰胺，以及门脉循环内神经酰胺水平 在代谢应激时期显著升高。因为这些数据，我们假设神经酰胺 内脏脂肪组织产生和分泌调节胰岛素敏感性和葡萄糖稳态 在肝脏中，作为传递营养状态或能量需求的生理机制。测试……的作用 在此肠肝轴对外周胰岛素敏感性的调节中，我们将完成以下目标： 首先，我们将确定产生损害糖耐量的神经酰胺池的主要组织； 第二，我们将研究与胰岛素抵抗有关的因素(如肿瘤坏死因子-α， 糖皮质激素)在神经酰胺合成中的调控；第三，我们将阐明其机制。 神经酰胺诱导肝脏胰岛素抵抗。总而言之，这些研究可能会揭示一种新的监管 在盛宴、饥荒或压力时调节外周胰岛素敏感性和能量利用的轴。

The peptide hormone insulin stimulates the uptake and storage of glucose and other nutrients into adipose tissue and skeletal muscle while simultaneously repressing glucose efflux from the liver. Insulin resistance occurs when a normal dose of the hormone is incapable of eliciting these anabolic responses, and the condition is a risk factor for cardiovascular disease, type 2 diabetes, and certain forms of cancer. Pathogenic factors implicated in the onset of insulin resistance (e.g. saturated fatty acids, tumor necrosis factor-alpha, and glucocorticoids) have been shown to selectively induce the synthesis of ceramide, a sphingolipid that has been shown to antagonize insulin action. We present findings indicating that the inhibition of ceramide synthesis in rodents ameliorates insulin resistance caused by saturated fats, glucocorticoids, and obesity. Moreover, we include preliminary data identifying the liver as a likely target of ceramide action, that white adipocytes secrete ceramide, and that ceramide levels within the portal circulation are markedly elevated during times of metabolic stress. Because of these data, we hypothesize that ceramide generated in and secreted from visceral adipose tissue modulates insulin sensitivity and glucose homeostasis in the liver as a physiological mechanism for communicating nutrient status or energy need. To test the role of this enterohepatic axis in the regulation of peripheral insulin sensitivity, we will complete the following aims: first, we will identify the primary tissues that produce the pools of ceramide which impaig glucose tolerance; second, we will investigate the role of factors implcated in insulin resistance (e.g. tumor necrosis factor-alpha, glucocorticoids) in the modulation of ceramide synthesis; and third, we will elucidate the mechanism underyling ceramide's induction of hepatic insulin resistance. Collectively, these studies could uncover a novel regulatory axis that modulates peripheral insulin sensitivity and energy utilization during times of feast, famine, or stress.