The Hepatokine Orosomucoid 2 Mediates Beneficial Metabolic Effects of Bile Acids.

Publisher: American Diabetes Association Country of Publication: United States NLM ID: 0372763 Publication Model: Print Cited Medium: Internet ISSN: 1939-327X (Electronic) Linking ISSN: 00121797 NLM ISO Abbreviation: Diabetes Subsets: MEDLINE

Publication: Alexandria, VA : American Diabetes Association
Original Publication: [New York, American Diabetes Association]

Bile Acids and Salts*/metabolism ; Orosomucoid*/metabolism ; Orosomucoid*/pharmacology; Mice ; Animals ; Mice, Inbred C57BL ; Obesity/genetics ; Obesity/metabolism ; Liver/metabolism ; Diet, High-Fat/adverse effects

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 current 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 with C57BL/6J control, partly due to the increased energy expenditure. However, when challenged with a HFD supplemented with cholic acid, Orm2-KO eliminated the antiobesity 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 interferon-γ/STAT1 activities in inguinal white adipose tissue 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 cross talk through ORM2 induction.
(© 2024 by the American Diabetes Association.)

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R01 DK125922 United States DK NIDDK NIH HHS; P30 CA125123 United States CA NCI NIH HHS; R56 DK128098 United States DK NIDDK NIH HHS; R01 DK126656 United States DK NIDDK NIH HHS; R01 DK122708 United States DK NIDDK NIH HHS; R01 DK114356 United States DK NIDDK NIH HHS; R01 DK121330 United States DK NIDDK NIH HHS; R01HL154720 United States HL NHLBI NIH HHS; P01 DK113954 United States DK NIDDK NIH HHS; R01 DK122796 United States DK NIDDK NIH HHS; P30CA125123 United States CA NCI NIH HHS; R01 HL154720 United States HL NHLBI NIH HHS

0 (Bile Acids and Salts)
0 (Orosomucoid)

Date Created: 20240206 Date Completed: 20240422 Latest Revision: 20240427

20240427

PMC11043061

10.2337/db23-0520

38320268