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.