Role of NgBR in regulating hepatic gluconeogenesis and insulin resistance

项目摘要 肥胖相关的2型糖尿病（T2 D）是美国人群中最常见的新兴代谢疾病。 胰岛素抵抗是2型糖尿病的重要病因。脂联素是一种脂肪细胞分泌的激素， 防止胰岛素抵抗的发展。最近的研究表明，脂联素降低了 表达的肝细胞生成酶，减弱葡萄糖的生产，并提高肝细胞的 胰岛素通过AMP活化蛋白激酶（AMPK）途径的作用。然而，弹性因素 维持肝脏中脂联素介导的AMPK活化所需的机制尚不清楚。这项建议 旨在填补我们关于NgBR在调节脂联素中作用的知识空白- 介导的AMPK激活和肝再生，并确定是否保留肝NgBR 表达足以预防肥胖相关的T2 D的发作。我们实验室的最新研究 提示NgBR在维持AMPK激活中起着以前未被认识的作用，因为NgBR结合 肝激酶B1（LKB 1-farn）的法尼基化形式，是AMPK的关键调节剂。初步结果显示 糖尿病动物模型和T2 D肥胖患者肝脏中NgBR表达降低 与非T2 D肥胖受试者相比。NgBR肝细胞特异性敲除（hepKO）小鼠显示出增加 在空腹葡萄糖水平中，并且在高脂肪饮食（HFD）喂养后将血浆葡萄糖进一步增加至T2 D水平。 肝细胞中NgBR缺陷损害AdipoRon（脂联素激动剂）诱导的AMPK活化 受体）。这些发现使我们提出了一个中心假设，即NgBR是一个所需的弹性因子 用于保持脂联素介导的胰岛素敏感性和预防肥胖引起的T2 D的发作，和 肝中NgBR依赖性调节系统的破坏导致肝再生调节受损 和胰岛素敏感性。我们的总体目标是阐明NgBR 增强脂联素介导的胰岛素敏感性和NgBR在胰岛素发病机制中的作用 阻力和T2 D。阐明NgBR调节LKB 1易位的机制将使我们能够 开发新的治疗策略，用于预防肥胖受试者中T2 D的发作。因此，我们将测试 我们的假设有两个特定的目标。目标1。确定NgBR调节的分子机制 肝脏中LKB 1-AMPK活化和脂联素信号通路。目标二。测定分子 NgBR调节胰岛素信号传导和肝脏再生的机制。成功完成 本提案中提出的研究将把NgBR描述为预防T2 D的弹性因素，并提供 T2 D预防或治疗的新见解。我们的研究将带来许多重大发现， 改善美国公民和其他患有T2 D的人的健康。我们的研究将揭示新的概念， 这些想法可以用于开发治疗胰岛素抵抗的疗法。因此，平移 这种应用的潜力是有前途的，与NIH的使命高度相关。

PROJECT SUMMARY Obesity-related type 2 diabetes (T2D) is the most common emerging metabolic disease in the US population. Insulin resistance is a key etiological factor of T2D. Adiponectin is an adipocyte-secreted hormone and prevents the development of insulin resistance. Recent studies show that adiponectin decreases the expression of hepatic gluconeogenic enzymes, attenuates glucose production, and enhances the hepatic effects of insulin through the AMP-activated protein kinase (AMPK) pathway. However, the resilience factors that are required to maintain adiponectin-mediated AMPK activation in the liver remain unclear. This proposal is designed to fill gaps in our knowledge concerning the role of NgBR in regulating adiponectin- mediated AMPK activation and hepatic gluconeogenesis, and to determine if preserving hepatic NgBR expression is sufficient to prevent the onset of obesity-related T2D. Recent studies from our laboratory suggest that NgBR plays a previously unrecognized role in maintaining AMPK activation because NgBR binds the farnesylated form of liver kinase B1 (LKB1-farn), a key regulator of AMPK. Preliminary results show that NgBR expression decreases in the liver of diabetic animal models and the liver of T2D obese patients compared to non-T2D obese subjects. NgBR hepatocyte-specific knockout (hepKO) mice showed an increase in fasting glucose levels and further increases plasma glucose to T2D levels after high-fat diet (HFD) feeding. NgBR deficiency in hepatocytes impairs AMPK activation induced by AdipoRon (an agonist of adiponectin receptors). These findings lead us to propose a central hypothesis that NgBR is a resilience factor required for preserving adiponectin-mediated insulin sensitivity and preventing the onset of obesity-caused T2D, and disruption of the NgBR-dependent regulation system in the liver leads to impairing gluconeogenesis regulation and insulin sensitivity. Our overall objectives are to elucidate the molecular mechanisms by which NgBR enhances adiponectin-mediated insulin sensitivity and the roles that NgBR plays in the pathogenesis of insulin resistance and T2D. Delineating the mechanisms by which NgBR regulates LKB1 translocation will allow us to develop new therapeutic strategies for preventing the onset of T2D in obese subjects. Accordingly, we will test our hypothesis with two specific aims. Aim 1. Determine the molecular mechanism by which NgBR regulates LKB1-AMPK activation and adiponectin signaling pathway in the liver. Aim 2. Determine the molecular mechanism by which NgBR regulates insulin signaling and hepatic gluconeogenesis. Successful completion of studies proposed in this proposal will characterize NgBR as a resilience factor for preventing T2D and provide novel insights for T2D prevention or treatment. Our studies will lead to many discoveries that will significantly improve the health of US citizens and others suffering from T2D. Our studies will reveal new concepts and ideas that can be used to develop therapies for treating insulin resistance. Accordingly, the translational potential of this application is promising and highly relevant to NIH's mission.