An Obesity-Induced Kinase that Regulates Adipose Homeostasis and Metabolic Diseases

一种调节脂肪稳态和代谢疾病的肥胖诱导激酶

• 批准号: 10398840
• 负责人: James C Lo
• 金额: $ 42.02万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-16 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398840
• 关键词: Ablation; Adipocytes; Adipose tissue; Cardiovascular Diseases; Cell Nucleus; Chronic; Country; Cues; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Dyslipidemias; Epidemic; Family; Functional disorder; Gene Expression; Genes; Goals; Golgi Apparatus; Health; Homeostasis; Hyperglycemia; Immune; Immune response; Inflammation; Inflammatory; Insulin Resistance; Knockout Mice; Light; Link; Liver diseases; Mass Spectrum Analysis; Medical; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Molecular; Molecular Mechanisms of Action; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Outcome Study; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Physiological; Play; Prevalence; Process; Protein-Serine-Threonine Kinases; Proteins; Public Health; Research; Research Proposals; Role; Testing; Time; blood glucose regulation; cancer type; chemokine; cytokine; diabetes pathogenesis; diet-induced obesity; energy balance; glucose tolerance; improved; insulin sensitivity; macrophage; member; mortality; new therapeutic target; non-alcoholic fatty liver disease; novel; novel therapeutics; overexpression; phosphoproteomics; programs; public health relevance; response; transcription factor

Project Summary/Abstract Obesity and type 2 diabetes mellitus (T2DM) have become national and global epidemics. The rising prevalence of obesity has dramatically increased the burden of dyslipidemia, specific types of cancer, nonalcoholic fatty liver disease, T2DM and cardiovascular diseases, the leading cause of mortality in the country. Recent studies have highlighted the intimate links between metabolic diseases and adipose tissue inflammation. Adipose inflammation plays an integral role in the development of metabolic syndrome. Adipose-immune interactions can have both positive and negative effects on adipose tissue homeostasis and whole body metabolism. What initiates adipocyte dysfunction and the inflammatory processes in obesity remain an enigma. This research proposal seeks to understand the molecular mechanisms that underlie adipocyte dysfunction and adipose inflammation. We identify fam20c as a novel regulator of adipose tissue inflammation and insulin resistance. Obesity induces expression of fam20c in adipocytes. Conversely, ablation of fam20c in adipocytes ameliorates hyperglycemia. In this proposal, we seek to assess the mechanistic links between insulin resistance and inflammation. We will pursue the following specific aims: 1. Determine the physiological and cellular mechanisms by fam20c regulates energy balance, glucose homeostasis and adipose tissue inflammation. 2. Dissect the molecular mechanism of action of the fam20c kinase in regulating inflammatory gene expression and insulin resistance. 3. We will test the hypothesis that adipose-specific ablation of fam20c can reverse established T2DM. The overall goal of these studies will shed light on how therapies directed against fam20c can be used to restore metabolic health in patients with T2DM.

项目概要/摘要 肥胖和 2 型糖尿病 (T2DM) 已成为全国和全球的流行病。崛起的 肥胖的流行极大地增加了血脂异常、特定类型癌症、 非酒精性脂肪肝、T2DM 和心血管疾病是人类死亡的主要原因 国家。最近的研究强调了代谢疾病与脂肪组织之间的密切联系 炎。脂肪炎症在代谢综合征的发展中起着不可或缺的作用。 脂肪-免疫相互作用可以对脂肪组织稳态产生积极和消极的影响 以及全身的新陈代谢。是什么引发了脂肪细胞功能障碍和炎症过程 肥胖仍然是一个谜。该研究计划旨在了解其分子机制 是脂肪细胞功能障碍和脂肪炎症的基础。我们认为 fam20c 是一种新型调节剂 脂肪组织炎症和胰岛素抵抗。肥胖会诱导脂肪细胞中 fam20c 的表达。 相反，消除脂肪细胞中的fam20c可改善高血糖。在本提案中，我们力求 评估胰岛素抵抗和炎症之间的机制联系。我们将追求以下目标 具体目标： 1.确定fam20c调节能量平衡的生理和细胞机制， 葡萄糖稳态和脂肪组织炎症。 2.剖析其作用的分子机制 fam20c 激酶调节炎症基因表达和胰岛素抵抗。 3. 我们将测试 假设脂肪特异性消融 fam20c 可以逆转已建立的 T2DM。总体目标为 这些研究将揭示如何使用针对 fam20c 的疗法来恢复代谢 T2DM 患者的健康状况。