Hepatokine Control of Metabolic Crosstalk and Insulin Resistance

肝因子控制代谢串扰和胰岛素抵抗

• 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
• 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

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 这个项目的主要目标是了解依赖NAD+的脱乙酰酶SIRT1是如何调节的 肝脏分泌的肝素及其如何减缓非酒精性脂肪肝的进展 疾病(NAFLD)和肥胖。肥胖或超重影响大约70%的美国成年人， 增加发展中的NAFLD和2型糖尿病的患病率。2型糖尿病是威胁生命的疾病 以外周胰岛素抵抗为特征的疾病，这种疾病使组织间的通讯失调 促进高血糖和血脂异常。然而，肝脏是否通过 作为内分泌器官通过分泌因子参与其他代谢组织的功能是一种新的 和未被开发的区域。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的缺失导致肥胖表型，表现为脂肪增加 质量和降低能量消耗。引人注目的是，基因表达谱分析确定成纤维细胞 生长因子21(FGF21)--一种由肝脏分泌的“瘦身因子”(称为肝细胞因子)--是最显著的 肝脏特异性SIRT1基因敲除(SIRT1 LKO)小鼠肝脏中下调的基因。因此，我们的中环 假设肝脏SIRT1调节的肝素对NAFLD和NAFLD有治疗意义 自分泌调节肝脂代谢和内分泌控制脂肪的肥胖 组织功能。由于SIRT1 LKO小鼠肝脏和循环中FGF21的水平显著降低， 我们选择研究肝细胞因子如FGF21在SIRT1作用中的作用。使用函数的增益和损耗 小鼠模型，这一中心假设将在三个特定的目标进行检验：1)确定肝脏 SIRT1通过刺激肝细胞因子FGF21保护全身胰岛素抵抗和代谢 肥胖症的异常；2)阐明肝细胞来源的SIRT1-SIRT1- FGF21信号在改善肝脏脂肪变性中发挥自分泌作用；3)研究肝脏 SIRT1诱导的FGF21激素对白色米色脂肪细胞和胰岛素抵抗的内分泌作用 脂肪组织。该项目是对单一组织或途径研究的创新，因此 可能揭示肝脏SIRT1缺陷单独导致肥胖的许多特征的机制。 该应用的创新方面还包括：SIRT1介导的调控的新概念 肝素代表肝脏和脂肪组织通讯的分子基础，这是一种新的机制 深入了解SIRT1通过一种涉及去乙酰化的机制调节FGF21的转录，以及 RNA测序和代谢组学分析的技术创新。总体而言，完成这项提议将 不仅提供了对以前未知的内分泌作用的基本洞察，肝脏在控制 此外，还将确定治疗非酒精性脂肪肝和肥胖症的新目标。