Hepatokine Control of Metabolic Crosstalk and Insulin Resistance

肝因子控制代谢串扰和胰岛素抵抗

基本信息

批准号：
9978049
负责人：
MENGWEI ZANG
金额：
$ 30.65万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978049
关键词：
Ablation Address Adipocytes Adipose tissue Adult Affect American Area Attenuated Biology Body Weight Cells Communication Data Deacetylase Deacetylation Defect Diabetes Mellitus Diet Disease Disease Progression Dyslipidemias Endocrine Endocrine Glands Energy Metabolism Estrogen receptor positive Fatty Liver Fatty acid glycerol esters Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Goals Hepatic Hepatocyte Homeostasis Hormones Human Hyperglycemia IRF4 gene Impairment Insulin Insulin Resistance Knock-out Knockout Mice Knowledge Life Light Link Lipids Liver Mediating Metabolic Metabolic Control Metabolic Diseases Metabolic dysfunction Metabolism Mission Molecular Mus National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity Epidemic Organ Overnutrition Overweight Pathogenesis Pathway interactions Peripheral Pharmaceutical Preparations Pharmacologic Substance Phenotype Prevalence Process Public Health Regulation Research Risk Role SIRT1 gene Series Signal Transduction Systems Biology Testing Therapeutic Therapeutic Effect Thermogenesis Thinness Tissues Transcript Transcriptional Regulation Weight maintenance regimen Work adipocyte differentiation autocrine base combat endoplasmic reticulum stress energy balance fibroblast growth factor 21 glucose metabolism improved in vivo innovation insight insulin sensitivity interest lipid biosynthesis lipid metabolism liver function liver metabolism loss of function metabolomics mouse model new therapeutic target non-alcoholic fatty liver disease novel overexpression oxidation paracrine pre-clinical preclinical study tool transcriptome sequencing

项目摘要

Project Summary The major goal of this project is to understand how the NAD+-dependent deacetylase SIRT1 regulates hepatokines that are secreted by the liver and how this process slows the progression of non-alcoholic fatty liver disease (NAFLD) and obesity. Obesity or being overweight affects approximately 70% of U.S. adults and increases the prevalence of developing NAFLD and Type 2 diabetes. Type 2 diabetes is a life-threatening disease characterized by peripheral insulin resistance, which dysregulates inter-tissue communication to promote hyperglycemia and dyslipidemia. However, whether the liver controls systemic metabolism by functioning as an endocrine organ to engage other metabolic tissues through secreted factors is a novel and under-explored area. Our preliminary studies reveal a series of novel and exciting observations that support our hypothesis. The loss of SIRT1 in the liver leads to an obese phenotype manifested by increased fat mass and decreased energy expenditure. Strikingly, gene expression profiling analyses identify that fibroblast growth factor 21 (FGF21)—a “lean factor” secreted by the liver (called hepatokine)—is the most markedly downregulated gene in the liver of liver-specific SIRT1 knockout (SIRT1 LKO) mice. Thus, our Central Hypothesis is that hepatic SIRT1-regulated hepatokines have therapeutic implications for NAFLD and obesity through the autocrine regulation of hepatic lipid metabolism and endocrine control of adipose tissue function. Because hepatic and circulating levels of FGF21 are remarkably decreased in SIRT1 LKO mice, we choose to study the role of hepatokines such as FGF21 in SIRT1 action. Using gain- and loss-of-function mouse models, this central hypothesis will be tested in three Specific Aims: 1) To determine whether hepatic SIRT1, via stimulating the hepatokine FGF21, protects against whole-body insulin resistance and metabolic abnormalities in obesity; 2) To elucidate the molecular mechanisms by which the hepatocyte-derived SIRT1- FGF21 signaling exerts an autocrine effect to ameliorate hepatic steatosis; and 3) To investigate whether hepatic SIRT1-induced FGF21 hormone has an endocrine effect on beige adipocytes and insulin resistance in white adipose tissue. This project is an innovative departure from the study of a single tissue or pathway and thus is likely to reveal the mechanisms by which hepatic SIRT1 defects alone give rise to many features of obesity. Innovative aspects of the application also include: the novel concept that SIRT1-mediated regulation of hepatokines represents the molecular basis for liver and adipose tissue communication, the new mechanistic insight into that SIRT1 regulates FGF21 transcription via a mechanism involving deacetylation, and the technical innovation of RNA-sequencing and metabolomics analyses. Overall, accomplishing this proposal will not only provide fundamental insight into a previously unrecognized endocrine role of the liver in controlling systemic and adipose tissue metabolism but will also identify new targets for treating NAFLD and obesity.

项目摘要该项目的主要目标是了解如何调节NAD+依赖性脱乙酰基酶SIRT1 肝脏分泌的肝动力细菌以及该过程如何减慢非酒精性脂肪肝的进展疾病（NAFLD）和肥胖症。肥胖或超重会影响约70％的美国成年人增加了发展NAFLD和2型糖尿病的患病率。 2型糖尿病是一种威胁生命的以周围胰岛素抵抗的特征疾病，该疾病失调与组织间交流失调促进高血糖和血脂异常。但是，肝脏是否通过通过分泌因素作为内分泌器官发挥作用，是一种新型和探索不足的区域。我们的初步研究揭示了一系列新颖而令人兴奋的观察结果支持我们的假设。肝脏中SIRT1的损失导致肥胖表型表现为脂肪增加质量和改善的能量消耗。令人惊讶的是，基因表达分析分析确定成纤维细胞生长因子21（FGF21）（肝脏分泌的“瘦因子”（称为肝素））是最明显的肝脏特异性SIRT1敲除（SIRT1 LKO）小鼠肝脏中的基因下调。那，我们的中心假设是肝1调节的肝动力油对NAFLD和肥胖通过肝炎脂质代谢和脂肪内分泌控制的自分泌调节组织功能。由于SIRT1 LKO小鼠的FGF21的肝和循环水平明显降低，所以我们选择研究肝素（例如FGF21）在SIRT1动作中的作用。使用功能丧失鼠标模型，该中心假设将以三个特定目的进行测试：1）确定是否肝 SIRT1通过刺激肝脏FGF21，可以防止全身胰岛素抵抗和代谢肥胖异常； 2）阐明肝细胞衍生的SIRT1-的分子机制 FGF21信号传导执行自分泌作用以改善肝脂肪变性。 3）调查hepati是否 SIRT1诱导的FGF21 Horsene对白色的米色脂肪细胞和胰岛素耐药性具有内分泌作用脂肪组织。该项目与对单个组织或途径的研究是一种创新的不同，因此可能揭示了仅肝脏SIRT1缺陷的机制，从而产生了许多肥胖特征。应用程序的创新方面还包括：SIRT1介导的调节的新颖概念肝因代表肝脏和脂肪组织通信的分子基础，新机械洞察SIRT1通过涉及脱乙酰化的机制调节FGF21的转录，并调节FGF21的转录 RNA测序和代谢组学分析的技术创新。总体而言，完成此建议将不仅可以对先前未知的肝脏中的内分泌作用提供基本见解系统性和脂肪组织代谢，但还将确定治疗NAFLD和肥胖症的新靶标。