THE ROLE OF HEPATOKINE ORM2 IN ADIPOSE TISSUE INFLAMMATION

肝因子 ORM2 在脂肪组织炎症中的作用

基本信息

批准号：
10615859
负责人：
Kangho Kim
金额：
$ 39万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615859
关键词：
Ablation Acceleration Adipocytes Adipose tissue Animal Model Anti-Inflammatory Agents Antidiabetic Drugs Antiinflammatory Effect Bile Acids Biliary Binding Body Composition Body Weight decreased CCR5 gene Cardiovascular Diseases Cell physiology Certification Cholic Acids Communication Coupled Data Diabetes Mellitus Diet Distal Endocrine Energy Metabolism Fatty Acids Feedback Functional disorder Genes Goals Hepatic Hormone secretion Immune Inflammation Inflammatory Inflammatory Response Insulin Interferon Type II Intervention Knockout Mice Link Lipids Liver Mediator Metabolic Metabolic Diseases Metabolic stress Metabolism Molecular Molecular Profiling Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Obese Mice Obesity Obesity Epidemic Operative Surgical Procedures Organ Orosomucoid Pathway interactions Peripheral Phenocopy Phenotype Regulation Role STAT1 protein Signal Transduction Testing Therapeutic Tissues United States Weight bariatric surgery chemokine receptor energy balance gamma-Chemokines improved innovation insight insulin sensitivity insulin sensitizing drugs liver injury metabolic phenotype mouse model novel obesity treatment overexpression receptor response surfactant function

项目摘要

ABSTRACT Bile acids (BAs) have recently emerged as metabolic regulators in obesity and type 2 diabetes. We discovered that the BA overload in farnesoid X receptor (FXR) and small heterodimer partner (SHP) double knockout mice unexpectedly exerts anti-obesity and anti-diabetic effects. Intriguingly, liver-specific FXR/SHP ablation phenocopies the global knockout mice with striking beneficial impacts on white adipose tissue (WAT) fatty acid utilization and inflammation. This raises the possibility that hepatic BA overload confers metabolic crosstalk between the liver and adipose tissues. Our preliminary results indicate that hepatic secretion of orosomucoid 2 (ORM2) is dramatically increased by not only BA overload, but also weight-loss Roux-en Y gastric bypass (RYGB) surgery. Hepatic Orm2 overexpression greatly reduces white adipose tissue (WAT) mass, coupled with marked improvement in whole-body insulin sensitivity. Importantly, ORM2 dampens proinflammatory interferon-gamma (IFNγ) and signal transducer and activator of transcription 1 (STAT1) signaling in WAT. These exciting data support the hypothesis that the hepatokine ORM2 exerts anti-inflammatory effects in WAT, which improves insulin sensitivity. The goal of this proposal is to critically test our hypothesis by challenging mouse models of ORM2 expression with various metabolic interventions. In Aim 1, we will determine the metabolic impact of hepatic ORM2 induction on WAT function in mouse models of obesity and type 2 diabetes. Aim 2 will determine the contribution of ORM2 to the broad beneficial effects of BA overload and RYGB surgery using Orm2-deficient mice. Lastly, Aim 3 will define anti-inflammatory effects of ORM2 on CCR5-IFNγ-STAT1 axis in WAT. Our studies will identify the molecular and cellular basis of hepatokine ORM2 function on WAT inflammation, which coordinately improves metabolic phenotypes. Ultimately, we expect to provide detailed insight into BA-induced liver-adipose tissue crosstalk with direct therapeutic potential for treating obesity and type 2 diabetes.

抽象的我们发现胆汁酸 (BA) 最近已成为肥胖和 2 型糖尿病的代谢调节剂。法尼醇 X 受体 (FXR) 和小异二聚体伴侣 (SHP) 双敲除小鼠中的 BA 超载令人惊奇的是，肝脏特异性 FXR/SHP 消融具有抗肥胖和抗糖尿病作用。表型复制的整体敲除小鼠对白色脂肪组织 (WAT) 脂肪酸具有显着的有益影响这增加了肝脏 BA 超载导致代谢串扰的可能性。我们的初步结果表明，肝脏分泌 Orosumucoid 2。 (ORM2) 不仅因 BA 超负荷而显着增加，而且减肥 Roux-en Y 胃绕道手术 (RYGB) 也会显着增加肝脏 Orm2 过度表达大大减少了白色脂肪组织 (WAT) 质量，并显着减少了白色脂肪组织 (WAT) 的质量。重要的是，ORM2 可以抑制促炎性干扰素-γ 的改善。 (IFNγ) 以及 WAT 中的信号转导子和转录激活子 1 (STAT1) 信号转导。支持肝因子 ORM2 在 WAT 中发挥抗炎作用的假设，从而改善该提案的目标是通过挑战小鼠模型来严格检验我们的假设。在目标 1 中，我们将确定各种代谢干预措施的 ORM2 表达。肥胖和 2 型糖尿病小鼠模型中肝 ORM2 诱导对 WAT 功能的影响将确定 Aim 2。 ORM2 对 BA 超载和使用 Orm2 缺陷的 RYGB 手术的广泛有益作用的贡献最后，目标 3 将定义 ORM2 对 WAT 中 CCR5-IFNγ-STAT1 轴的抗炎作用。将确定肝因子 ORM2 对 WAT 炎症的作用的分子和细胞基础，最终，我们期望提供对 BA 诱导的详细了解。肝脏-脂肪组织串扰具有治疗肥胖和 2 型糖尿病的直接治疗潜力。