THE ROLE OF HEPATOKINE ORM2 IN ADIPOSE TISSUE INFLAMMATION

摘要 胆汁酸（BA）最近已成为肥胖和2型糖尿病的代谢调节剂。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， 出乎意料地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 表型模仿了对白色脂肪组织（WAT）脂肪酸具有显著有益影响的整体敲除小鼠 利用和炎症。这增加了肝脏BA过载引起代谢串扰的可能性 在肝脏和脂肪组织之间。我们的初步结果表明，肝分泌的类粘蛋白2 （ORM 2）不仅通过BA过载，而且通过减肥Roux-en Y胃旁路（RYGB）显著增加 手术肝脏Orm 2过表达大大减少了白色脂肪组织（WAT）质量，同时伴有显著的 改善全身胰岛素敏感性。重要的是，ORM 2抑制促炎性干扰素-γ (IFNγ）和信号转导和转录激活因子1（STAT 1）信号转导。这些激动人心的数据 支持肝细胞因子ORM 2在WAT中发挥抗炎作用的假设， 胰岛素敏感性这项提议的目的是通过挑战小鼠模型来严格检验我们的假设。 ORM 2表达与各种代谢干预。在目标1中，我们将确定 肝脏ORM 2诱导对肥胖和2型糖尿病小鼠模型WAT功能的影响目标2将决定 ORM 2对BA过载和使用Orm 2缺陷的RYGB手术的广泛有益效果的贡献 小鼠最后，目的3将确定ORM 2对WAT中CCR 5-IFNγ-STAT 1轴的抗炎作用。我们的研究 将确定肝细胞因子ORM 2对WAT炎症的分子和细胞基础， 协同改善代谢表型。最终，我们希望提供详细的洞察BA诱导 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。

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.