THE ROLE OF HEPATOKINE ORM2 IN ADIPOSE TISSUE INFLAMMATION

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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.