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.

抽象的胆汁酸（BAS）最近成为肥胖症和2型糖尿病的代谢调节剂。我们发现了 Farnesoid X受体（FXR）和小型异二聚体伴侣（SHP）双基因敲除小鼠中的BA超载出乎意料地发挥抗肥胖和抗糖尿病作用。有趣的是，肝特异性FXR/SHP消融该表opies全球敲除小鼠对白色脂肪组织（WAT）脂肪酸产生巨大有益影响利用和炎症。这增加了Hepatitic BA超负荷承认代谢串扰的可能性在肝脏和脂肪组织之间。我们的初步结果表明，口感核酸2的肝分泌2 （ORM2）不仅可以大大增加BA的超载，还增加了减肥roux-en y胃旁路（RYGB）外科手术。肝ORM2过表达大大降低了白色脂肪组织（WAT）质量，并与标记改善全身胰岛素敏感性。重要的是，ORM2会抑制促炎干扰素γ （IFNγ）和信号传感器和转录1（STAT1）信号的激活因子在WAT中。这些令人兴奋的数据支持以下假设胰岛素灵敏度。该提案的目的是通过挑战鼠标模型来批判性地检验我们的假设 ORM2表达各种代谢干预措施。在AIM 1中，我们将确定肥胖和2型糖尿病小鼠模型中WAT功能的肝ORM2诱导。 AIM 2将确定 ORM2对使用ORM2缺乏效率的BA超载和RYGB手术的广泛有益作用的贡献老鼠。最后，AIM 3将定义ORM2对WAT中CCR5-IFNγ-Stat1轴的抗炎作用。我们的研究将确定肝素ORM2在WAT注射中功能的分子和细胞基础，该功能协调改善代谢表型。最终，我们期望对BA诱导的详细见解具有直接治疗肥胖症和2型糖尿病的直接治疗潜力的肝磷脂组织串扰。