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。出人意料的是，我们发现法尼类X受体(FXR)和小杂二聚体伙伴(SHP)双基因敲除小鼠的BA超载具有抗肥胖和抗糖尿病的作用。耐人寻味的是，肝脏特异性FXR/SHP消融术模仿了全球基因敲除小鼠的表型，对白色脂肪组织(WAT)脂肪酸的利用和炎症有显著的有益影响。这增加了肝脏BA超负荷导致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BA超负荷，而且减重Roux-en Y胃旁路手术(RYGB)显著增加了肝脏ORM2的分泌，肝脏ORM2的表达改善了能量平衡。Orm2的过度表达大大减少了白色脂肪组织(WAT)的质量，并伴随着全身胰岛素敏感性。重要的是，ORM2抑制WAT中的促炎干扰素-γ(γ)信号。这些令人兴奋的数据支持这样的假设，即诱导肝细胞因子ORM2在WAT中发挥抗炎作用，从而允许胰岛素敏感性和 减少肥胖。这项提议的目标是通过用饮食和胆汁酸应激挑战ORM2表达的小鼠模型来批判性地检验我们的假设。在目标1中，我们将描述诱导肝脏ORM2在脂肪细胞和脂肪组织中的代谢影响。目标2将定义ORM2如何在OrM2缺陷小鼠中介导BA超负荷和RYGB手术的有益影响。最后，目标3将确定ORM2是否抑制WAT中促炎症的CCR5-干扰素γ-STAT1轴。我们的研究将探索一种新的肝素ORM2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症和2型糖尿病治疗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.