THE ROLE OF HEPATOKINE ORM2 IN ADIPOSE TISSUE INFLAMMATION

肝因子 ORM2 在脂肪组织炎症中的作用

• 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
• 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

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，我们发现法内脂类X受体（FXR）和小异源二聚体伴侣（SHP）双敲除小鼠的BA过载具有抗肥胖和抗糖尿病的作用。有趣的是，肝脏特异性FXR/SHP消融术显示了全球基因敲除小鼠对白色脂肪组织（WAT）脂肪酸利用和炎症的显著有益影响。这增加了肝脏BA过载导致肝脏和脂肪组织之间代谢串扰的可能性。我们的初步结果表明，肝脏orosomucoid 2 （ORM2）的分泌不仅在BA超载的情况下显著增加，而且在减肥的Roux-en - Y胃旁路（RYGB）手术中也显著增加，肝脏ORM2的表达改善了能量平衡。Orm2过表达大大降低了白色脂肪组织（WAT）质量，同时降低了全身胰岛素敏感性。重要的是，ORM2抑制WAT中的促炎干扰素γ (IFNγ)信号。这些令人兴奋的数据支持了肝因子ORM2的诱导在WAT中发挥抗炎作用的假设，这使得胰岛素敏感性和