Role of NgBR in regulating hepatic gluconeogenesis and insulin resistance

项目总结 肥胖相关的2型糖尿病(T2D)是美国人群中最常见的新陈代谢疾病。 胰岛素抵抗是T2D的关键致病因素。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，脂联素可以降低 肝糖异生酶的表达，减少葡萄糖的产生，增强肝脏 胰岛素通过AMP激活的蛋白激酶(AMPK)途径发挥作用。然而，弹性因素 在肝脏中维持脂联素介导的AMPK激活所需的分子仍不清楚。这项建议 旨在填补我们关于NGBR在调节脂联素中的作用的知识空白。 介导AMPK活化和肝脏糖异生，并确定是否保存肝脏NGBR 表达足以防止肥胖相关的T2D的发病。我们实验室的最新研究 提示ngbr在维持AMPK激活方面起着以前未被认识到的作用，因为ngbr结合 法呢化形式的肝激酶B1(LKB1-FARN)是AMPK的关键调节因子。初步结果显示， NGBR在糖尿病动物模型肝脏和T2D肥胖患者肝脏中的表达减少 与非T2D肥胖受试者相比。NGBR肝细胞特异性基因敲除(HepKO)小鼠表现出增加 在高脂饮食(HFD)喂养后，空腹血糖水平下降，血糖水平进一步升高至T2D水平。 肝细胞NGBR缺乏影响脂联素激动剂AdipoRon诱导的AMPK活性 受体)。这些发现导致我们提出了一个中心假设，即ngbr是一个所需的弹性因素。 为了保持脂联素介导的胰岛素敏感性和预防肥胖引起的T2D的发病，以及 肝脏中依赖NGBR的调节系统的破坏导致糖异生调节受损 和胰岛素敏感性。我们的总体目标是阐明ngbr的分子机制。 增强脂联素介导的胰岛素敏感性及NGBR在胰岛素发病机制中的作用 阻力和T2D。描绘NGBR调节LKB1易位的机制将使我们能够 开发新的治疗策略以预防肥胖者T2D的发病。因此，我们将测试 我们的假设有两个具体目的。目的1.确定NGBR调控的分子机制 肝脏中LKB1-AMPK激活与脂联素信号通路目的2.确定分子 NGBR调节胰岛素信号和肝脏糖异生的机制。成功完成 这项建议中提出的研究将把ngbr描述为预防t2d的复原力因素，并提供 对T2D预防或治疗的新见解。我们的研究将导致许多发现，这些发现将显著 改善美国公民和其他患有T2D的人的健康。我们的研究将揭示新的概念和 可以用来开发治疗胰岛素抵抗的疗法的想法。因此，翻译后的 这一应用的潜力是有前景的，并且与NIH的任务高度相关。

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.