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: 10596140
• 负责人: QING MIAO
• 金额: $ 59.25万
• 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/10596140
• 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; Hormone secretion; Hormones; Human; Impairment; Insulin; Insulin Resistance; Knockout Mice; Knowledge; Laboratories; 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 Secretion; Proteins; Regulation; Research; Risk Factors; Role; STK11 gene; Signal Induction; Signal Pathway; Signal Transduction; System; Testing; Thinness; Transcript; United States National Institutes of Health; adiponectin; design; diabetic; disability; epidemiologic data; evidence base; farnesylation; 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; resilience factor; 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.

项目概要 与肥胖相关的 2 型糖尿病 (T2D) 是美国人群中最常见的新出现的代谢性疾病。 胰岛素抵抗是T2D的关键病因。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，脂联素可降低 肝糖异生酶的表达，减弱葡萄糖的产生，增强肝功能 胰岛素通过 AMP 激活蛋白激酶 (AMPK) 途径发挥作用。但韧性因素 维持肝脏中脂联素介导的 AMPK 激活所需的机制仍不清楚。这个提议 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 激活和肝脏糖异生，并确定是否保留肝脏 NgBR 表达足以预防肥胖相关 T2D 的发生。我们实验室的最新研究 表明 NgBR 在维持 AMPK 激活方面发挥着以前未被认识到的作用，因为 NgBR 结合 肝激酶 B1 (LKB1-farn) 的法呢基化形式，是 AMPK 的关键调节因子。初步结果表明 糖尿病动物模型肝脏和 T2D 肥胖患者肝脏中 NgBR 表达降低 与非 T2D 肥胖受试者相比。 NgBR 肝细胞特异性敲除 (hepKO) 小鼠表现出增加 空腹血糖水平，并在高脂饮食（HFD）喂养后进一步将血浆血糖升高至 T2D 水平。 肝细胞中的 NgBR 缺陷会损害 AdipoRon（脂联素激动剂）诱导的 AMPK 激活 受体）。这些发现使我们提出一个中心假设，即 NgBR 是所需的弹性因素 用于保持脂联素介导的胰岛素敏感性并预防肥胖引起的 T2D 的发作，以及 肝脏中 NgBR 依赖性调节系统的破坏会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以及 NgBR 在胰岛素发病机制中的作用 电阻和 T2D。描述 NgBR 调节 LKB1 易位的机制将使我们能够 开发新的治疗策略来预防肥胖受试者发生 T2D。据此，我们将测试 我们的假设有两个具体目标。目标1.确定NgBR调节的分子机制 肝脏中 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。顺利完成 本提案中提出的研究将把 NgBR 描述为预防 T2D 的弹性因素，并提供 T2D 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 T2D 的人的健康。我们的研究将揭示新概念 可用于开发治疗胰岛素抵抗的疗法的想法。因此，翻译 该应用的潜力是有前景的，并且与 NIH 的使命高度相关。