Role of NgBR in regulating hepatic gluconeogenesis and insulin resistance

NgBR 在调节肝糖异生和胰岛素抵抗中的作用

• 批准号: 10418590
• 负责人: QING MIAO
• 金额: $ 58.56万
• 依托单位: NYU LONG ISLAND SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418590
• 关键词: 5' -AMP-activated protein kinase; Adipocytes; Agonist; Animal Model; Attenuated; Blood Glucose; Cell membrane; Complex; Data; Development; Diabetes Mellitus; Diabetes prevention; Diabetic mouse; Enzymes; Etiology; Gene Expression Profile; Gluconeogenesis; Glucose; Health; Hepatic; Hepatocyte; High Fat Diet; Hormones; Human; Impairment; Insulin; Insulin Resistance; Knockout Mice; Knowledge; Laboratories; Lead; Liver; Mediating; Metabolic Diseases; Mission; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Pathogenesis; Pathway interactions; Patients; Plasma; Play; Population; Prediabetes syndrome; Prevention therapy; Protein Kinase; Proteins; Regulation; Research; Risk Factors; Role; STK11 gene; Signal Pathway; Signal Transduction; System; Testing; Thinness; Transcript; United States National Institutes of Health; adiponectin; base; design; diabetic; disability; epidemiologic data; evidence base; fasting glucose; feeding; glucose production; hepatic gluconeogenesis; improved; insight; insulin sensitivity; insulin signaling; novel; novel strategies; novel therapeutic intervention; novel therapeutics; obese patients; obese person; obesity prevention; preservation; prevent; receptor; receptor binding; receptor expression; resilience; restoration; therapy development; translational potential; 5' -AMP-activated protein kinase; Adipocytes; Agonist; Animal Model; Attenuated; Blood Glucose; Cell membrane; Complex; Data; Development; Diabetes Mellitus; Diabetes prevention; Diabetic mouse; Enzymes; Etiology; Gene Expression Profile; Gluconeogenesis; Glucose; Health; Hepatic; Hepatocyte; High Fat Diet; Hormones; Human; Impairment; Insulin; Insulin Resistance; Knockout Mice; Knowledge; Laboratories; Lead; Liver; Mediating; Metabolic Diseases; Mission; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Pathogenesis; Pathway interactions; Patients; Plasma; Play; Population; Prediabetes syndrome; Prevention therapy; Protein Kinase; Proteins; Regulation; Research; Risk Factors; Role; STK11 gene; Signal Pathway; Signal Transduction; System; Testing; Thinness; Transcript; United States National Institutes of Health; adiponectin; base; design; diabetic; disability; epidemiologic data; evidence base; fasting glucose; feeding; glucose production; hepatic gluconeogenesis; improved; insight; insulin sensitivity; insulin signaling; novel; novel strategies; novel therapeutic intervention; novel therapeutics; obese patients; obese person; obesity prevention; preservation; prevent; receptor; receptor binding; receptor expression; resilience; restoration; therapy development; translational potential

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.

项目摘要 与肥胖相关的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的关键病因。脂联素是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 肝糖原性酶的表达，减轻葡萄糖的产生并增强肝 胰岛素通过AMP激活蛋白激酶（AMPK）途径的作用。但是，弹性因素 维持脂肪蛋白介导的AMPK激活所需的是尚不清楚。这个建议 旨在填补我们关于NGBR在调节脂联蛋白 - 介导的AMPK激活和肝糖异生，并确定是否保留肝NGBR 表达足以防止肥胖相关T2D的发作。我们实验室的最新研究 表明NGBR在维持AMPK激活中起着先前未认识的作用，因为NGBR结合 肝激酶B1（LKB1-FARN）的法尼化形式，AMPK的关键调节剂。初步结果表明 NGBR表达在糖尿病动物模型的肝脏和T2D肥胖患者的肝脏中降低 与非T2D肥胖受试者相比。 NGBR肝细胞特异性敲除（HEPKO）小鼠显示出增加 在禁食葡萄糖水平并进一步增加了高脂饮食（HFD）喂养后血浆葡萄糖为T2D水平。 肝细胞中的NGBR缺乏会损害Adiporon诱导的AMPK激活（脂联蛋白的激动剂 受体）。这些发现使我们提出了一个核心假设，即NGBR是所需的弹性因素 用于保留脂联素介导的胰岛素敏感性并防止肥胖引起的T2D发作 肝脏中NGBR依赖性调节系统的破坏会导致糖异生的调节 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以及NGBR在胰岛素发病机理中的作用 电阻和T2D。描述NGBR调节LKB1易位的机制将使我们能够 制定新的治疗策略来防止肥胖受试者中T2D的发作。因此，我们将测试 我们的假设具有两个具体的目标。目标1。确定NGBR调节的分子机制 肝脏中的LKB1-AMPK激活和脂联素信号通路。目标2。确定分子 NGBR调节胰岛素信号传导和肝糖异生的机制。成功完成 该提议中提出的研究将表征NGBR是防止T2D并提供的弹性因素 T2D预防或治疗的新颖见解。我们的研究将导致许多发现将大大发现 改善美国公民和其他患有T2D的其他人的健康。我们的研究将揭示新的概念和 可用于开发治疗胰岛素抵抗的疗法的想法。因此，翻译 该应用的潜力是有希望的，并且与NIH的使命高度相关。