American Diabetes Association
ORM2_in_Obesity_Supple_Diabetes_Revised2.pdf (604.38 kB)

The hepatokine orosomucoid 2 mediates beneficial metabolic effects of bile acids

Download (604.38 kB)
posted on 2024-02-06, 21:40 authored by Sung Ho Lee, Ji Ho Suh, Mi Jeong Heo, Jong Min Choi, Yang Yang, Hyun-Jung Jung, Zhanguo Gao, Yongmei Yu, Sung Yun Jung, Mikhail G. Kolonin, Aaron R. Cox, Sean M. Hartig, Holger K. Eltzschig, Cynthia Ju, David D. Moore, Kang Ho Kim

Bile acids (BAs) are pleiotropic regulators of metabolism. Elevated levels of hepatic and circulating BAs improve energy metabolism in peripheral organs, but the precise mechanisms underlying the metabolic benefits and harm still need to be fully understood. In the present study, we identified orosomucoid 2 (ORM2) as a liver-secreted hormone (i.e., hepatokine) induced by BAs and investigated its role in BA-induced metabolic improvements in mouse models of diet-induced obesity. Contrary to our expectation, under a high-fat diet (HFD), our Orm2 knockout (Orm2-KO) exhibited a lean phenotype compared to C57BL/6J control, partly due to the increased energy expenditure. However, when challenged with HFD supplemented with cholic acid (HFDCA), Orm2-KO eliminated the anti-obesity effect of BAs, indicating that ORM2 governs BA-induced metabolic improvements. Moreover, hepatic ORM2 overexpression partially replicated BA effects by enhancing insulin sensitivity. Mechanistically, ORM2 suppressed IFNγ/STAT1 activities in inguinal WAT (iWAT) depots, forming the basis for anti-inflammatory effects of BAs and improving glucose homeostasis. In conclusion, our study provides new insights into the molecular mechanisms of BA-induced liver-adipose crosstalk through ORM2 induction.


This work was supported by the NIH R01DK126656 (to KHK) and partly by R01DK125922 (to MGK), R56DK128098 (to ARC), R01DK114356 (to SMH), R01HL154720 (to HKE), R01DK122796 (to CJ and HKE), R01DK121330 (to CJ), R01DK122708 (to CJ), and P01DK113954 (to DDM). It was also funded by the Assistant Secretary of Defense for Health Affairs endorsed by the DOD PRMRP Discovery Award W81XWH-18-1-0126 (to KHK), the American Heart Association Career Development Award 19CDA34660196 (to KHK), and the Baylor College of Medicine Nutrition and Obesity Pilot and Feasibility Fund (to KHK and ARC). MGK is supported by the Bovay Foundation and the Levy-Longenbaugh Fund. Core services at Baylor College of Medicine utilized in this project were supported with funding from NCI P30CA125123 and the Advanced Technology Cores used for this study are Genetically Engineered Rodent Models, Protein and Monoclonal Antibody Production, Mouse Metabolic and Phenotyping, and Gene Vector Cores.


Usage metrics



    Ref. manager