THE ROLE OF HEPATOKINE ORM2 IN ADIPOSE TISSUE INFLAMMATION

胆汁酸（BA）调节肥胖和2型糖尿病的代谢并发症。出乎意料的是，我们发现在法尼醇X受体（FXR）和小异源二聚体伴侣（SHP）双敲除小鼠中BA过载发挥抗肥胖和抗糖尿病作用。有趣的是，肝脏特异性FXR/SHP消融表型模仿了整体敲除小鼠，对白色脂肪组织（WAT）脂肪酸利用和炎症具有显著的有益影响。这提出了肝BA过载赋予肝脏和脂肪组织之间的代谢串扰的可能性。我们的初步研究结果表明，不仅BA过载，而且减肥Roux-en Y胃旁路（RYGB）手术，肝脏分泌orosomucoid 2（ORM 2）显着增加，肝脏ORM 2表达改善能量平衡。Orm 2过表达极大地减少了白色脂肪组织（WAT）质量，同时降低了全身胰岛素敏感性。重要的是，ORM 2抑制WAT中的促炎性干扰素-γ（IFNγ）信号传导。这些令人兴奋的数据支持了肝细胞因子ORM 2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 减少肥胖。该提案的目标是通过挑战具有饮食和胆汁酸应激的ORM 2表达的小鼠模型来严格检验我们的假设。在目标1中，我们将描述脂肪细胞和脂肪组织中肝脏ORM 2诱导的代谢影响。目的2将使用Orm 2缺陷小鼠来定义ORM 2如何介导BA过载和RYGB手术的有益作用。最后，目标3将确定ORM 2是否抑制WAT中的促炎性CCR 5-IFNγ-STAT 1轴。我们的研究将探索一种新型肝细胞因子ORM 2的代谢益处，并提供对肝脏-脂肪组织串扰的详细见解。最终，我们希望发现一种具有治疗肥胖和2型糖尿病潜力的组织串扰途径。

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.