LEPTIN AND PERIPHERAL GLUCOSE METABOLISM

瘦素和外周葡萄糖代谢

• 批准号: 6164563
• 负责人: Ruth B Harris
• 金额: $ 2.16万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6164563
• 关键词: SDS polyacrylamide gel electrophoresis; adipocytes; dietary lipid; fatty acid metabolism; glucose metabolism; glucose tolerance; growth factor receptors; hormone receptor; hormone regulation /control mechanism; insulin dependent diabetes mellitus; insulin sensitivity /resistance; laboratory mouse; leptin; liver metabolism; nutrition related tag; obesity; pancreatic islet function; protein structure; protein tyrosine kinase; receptor expression; western blottings

Leptin is a protein produced by adipose tissue and hypothesized to be a circulating lipostatic factor (82). Our preliminary data shows that leptin infusion into normal mice inhibits insulin release in response to a glucose challenge, induces insulin resistance in adipocytes, but promotes insulin-stimulated glycogen synthesis in muscle. An impaired acute insulin release in response to glucose is a risk factor for development of non-insulin dependent diabetes (NIDDM) (25) and increased insulin-stimulated glycogen synthesis in muscle is characteristic of the early metabolic changes observed during the development of insulin resistance in high-fat fed rats (48). We hypothesize that leptin mediates development of an impaired glucose tolerance that precedes early NIDDM by suppressing glucose stimulated insulin release and modifying insulin-stimulated glucose utilization in a tissue and pathway specific manner. Experiments described in Specific Aim 1 will examine the effects of leptin infusion on glucose and fatty acid metabolism of the three major insulin-responsive tissues in lean mice and will determine whether the effects on insulin responsiveness are mediated by the long-form leptin receptor, OB-Rb. Experiments in Specific Aim 2 will investigate the role of leptin in modifying insulin signaling to determine whether leptin changes tissue insulin receptor number, glucose transporter number or translocation, and insulin receptor tyrosine kinase activity. These processes represent the first stage of the insulin signaling cascade and the results of these experiments will determine how leptin modifies the initial stages of insulin signaling to change peripheral tissue glucose utilization. The studies described in this proposal will provide the information required to understand how leptin treatment modifies insulin responsiveness in peripheral tissues and the mechanisms by which this is achieved. It is essential to elucidate this aspect of leptin activity as it may account for the increased risk of development of glucose intolerance that is associated with obesity.

瘦素是一种由脂肪组织产生的蛋白质，推测是 循环脂肪抑制因子 (82)。 我们的初步数据表明 瘦素输注到正常小鼠体内会抑制胰岛素释放 应对葡萄糖挑战，诱导脂肪细胞中的胰岛素抵抗，但是 促进肌肉中胰岛素刺激的糖原合成。 一个受损的 响应葡萄糖的急性胰岛素释放是以下危险因素 非胰岛素依赖型糖尿病 (NIDDM) (25) 的发展和增加 肌肉中胰岛素刺激的糖原合成是 胰岛素开发过程中观察到的早期代谢变化 高脂肪喂养大鼠的抵抗力（48）。 我们假设瘦素 介导葡萄糖耐量受损的发展 早期 NIDDM 通过抑制葡萄糖刺激的胰岛素释放和 改变组织和途径中胰岛素刺激的葡萄糖利用 具体方式。 具体目标 1 中描述的实验将检查 瘦素输注对葡萄糖和脂肪酸代谢的影响 瘦小鼠的三个主要胰岛素反应组织 确定对胰岛素反应性的影响是否由以下因素介导 长型瘦素受体 OB-Rb。 具体目标 2 的实验 将研究瘦素在改变胰岛素信号传导中的作用 确定瘦素是否改变组织胰岛素受体数量、葡萄糖 转运蛋白数量或易位，以及胰岛素受体酪氨酸 激酶活性。 这些过程代表了第一阶段 胰岛素信号级联反应和这些实验的结果将 确定瘦素如何改变胰岛素信号传导的初始阶段 改变外周组织葡萄糖的利用。 研究描述 在本提案中将提供了解如何进行所需的信息 瘦素治疗改变外周组织的胰岛素反应性 以及实现这一目标的机制。至关重要的是 阐明瘦素活性的这一方面，因为它可能解释 相关的葡萄糖不耐受的风险增加 与肥胖。