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：
10459962
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/10459962
关键词：
Ablation Adipocytes Adipose tissue Animal Model Antidiabetic Drugs Antiinflammatory Effect Bile Acids Biliary Body Composition Body Weight decreased CCR5 gene Cardiovascular Diseases Cholic Acids Communication Coupled Data Diet Distal Energy Metabolism Fatty Acids Feedback Functional disorder Genes Goals Hepatic Hormones Immunophenotyping Inflammation Inflammatory Response Insulin Resistance Interferon Type II Knock-out Knockout Mice Link Lipids Liver Mediating Mediator of activation protein 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 PTPN11 gene Pathway interactions Peripheral Phenocopy Phenotype Physiological Regulation Role STAT1 gene Signal Transduction Testing Therapeutic Tissues United States acid stress bariatric surgery base diabetic energy balance improved insight insulin sensitivity insulin sensitizing drugs liver injury mouse model novel novel therapeutic intervention obesity treatment overexpression receptor response

项目摘要

Bile acids (BAs) modulate metabolic complications of obesity and type 2 diabetes. Unexpectedly, we discovered that the BA overload in farnesoid X receptor (FXR) and small heterodimer partner (SHP) double knockout mice 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, and that hepatic ORM2 expression improves energy balance. Orm2 overexpression greatly reduces white adipose tissue (WAT) mass, coupled with whole-body insulin sensitivity. Importantly, ORM2 dampens proinflammatory interferon-gamma (IFNγ) signaling in WAT. These exciting data support the hypothesis that induction of the hepatokine ORM2 exerts anti-inflammatory effects in WAT, which allows insulin sensitivity and decreases obesity. The goal of this proposal is to critically test our hypothesis by challenging mouse models of ORM2 expression with diet and bile acid stress. In Aim 1, we will delineate the metabolic impact of hepatic ORM2 induction in adipocytes and adipose tissues. Aim 2 will define how ORM2 mediates beneficial effects of BA overload and RYGB surgery using Orm2-deficient mice. Lastly, Aim 3 will establish whether ORM2 inhibits the proinflammatory CCR5-IFNγ-STAT1 axis in WAT. Our studies will explore the metabolic benefits of a novel hepatokine, ORM2, and provide detailed insights into liver-adipose tissue crosstalk. Ultimately, we expect to discover a tissue crosstalk pathway with therapeutic potential for treating obesity and type 2 diabetes.

胆汁酸（BAS）调节肥胖和2型糖尿病的代谢并发症。出乎意料的是，我们发现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超负荷会发挥抗肥胖和抗糖尿病作用。有趣的是，肝脏特异性FXR/SHP消融表型全球敲除小鼠对白色脂肪组织（WAT）脂肪酸利用率和炎症产生了巨大的有益影响。这增加了肝BA超负荷承认肝脏和脂肪组织之间的代谢串扰的可能性。我们的初步结果表明，不仅可以通过BA超载，而且还可以大大增加类口类糖体2（ORM2）的肝分泌，还可以大大增加，而且减轻体重可能会减轻体重，而减肥roux-en Y胃旁路（RYGB）手术，并且肝ORM2表达表达可提高能量平衡。 ORM2的过表达大大降低了白色脂肪组织（WAT）质量，并与全身胰岛素敏感性结合使用。重要的是，ORM2在WAT中抑制促炎性干扰素 - γ（IFNγ）信号。这些令人兴奋的数据支持以下假设：诱导肝脏ORM2在WAT中执行抗炎作用，这允许胰岛素敏感性和减少肥胖。该提案的目的是通过饮食和胆汁酸应激的ORM2表达的挑战小鼠模型进行批判性检验我们的假设。在AIM 1中，我们将描述脂肪细胞和脂肪组织中肝ORM2诱导的代谢影响。 AIM 2将定义ORM2如何使用ORM2缺陷小鼠介导BA过载和RYGB手术的有益作用。最后，AIM 3将确定ORM2是否抑制WAT中的促炎CCR5-IFNγ-Stat1轴。我们的研究将探索新型肝素ORM2的代谢益处，并为肝磷液组织串扰提供详细的见解。最终，我们期望发现具有治疗肥胖症和2型糖尿病的治疗潜力的组织串扰途径。