The adipokine orosomucoid alleviates adipose tissue fibrosis via the AMPK pathway  

作　　者：Peng-yuan Wang Jia-yi Feng Zhen Zhang Yi Chen Zhen Qin Xian-min Dai Jie Wei Bo-han Hu Wei-dong Zhang Yang Sun Xia Liu 

机构地区：[1]School of Pharmacy,Second Military Medical University/Naval Medical University,Shanghai 200433,China

出　　处：《Acta Pharmacologica Sinica》2022年第2期367-375,共9页中国药理学报（英文版）

基　　金：This study was supported by grants from the National Natural Science Foundation of China(Nos.81773726,82073907,and 82073842);the Shanghai Science and Technology Innovation Action Plan(Nos.20ZR1470100,18431900800,and 20S11902700);the National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program,China(No.2018ZX09711002-003-015).

摘　　要：The excess deposition of underlying extracellular matrix (ECM) in adipose tissue is defined as adipose tissue fibrosis that is a major contributor to metabolic disorder such as obesity and type 2 diabetes. Anti-fibrosis therapy has received much attention in the treatment of metabolic disorders. Orosomucoid (ORM) is an acute-phase protein mainly produced by liver, which is also an adipokine. In this study, we investigated the effects of ORM on adipose tissue fibrosis and the potential mechanisms. We showed that ORM1-deficient mice exhibited an obese phenotype, manifested by excessive collagen deposition in adipose tissues and elevated expression of ECM regulators such as metalloproteinases (MMP-2, MMP-13, MMP-14) and tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3). Administration of exogenous ORM (50 mg· kg−1· d−1, ip) for 7 consecutive days in high-fat diet (HFD)-fed mice and leptin receptor (LepR)-deficient db/db mice attenuated these abnormal expressions. Meanwhile, ORM administration stimulated AMP-activated protein kinase (AMPK) phosphorylation and decreased transforming growth factor-β1 (TGF-β1) level in adipose tissues of the mice. In TGF-β1-treated 3T3-L1 fibroblasts, ORM (10 μg/mL) improved the impaired expression profiles of fibrosis-related genes, whereas a selective AMPK inhibitor dorsomorphin (1 μmol/mL) abolished these effects. Together, our results suggest that ORM exerts a direct anti-fibrosis effect in adipose tissue via AMPK activation. ORM is expected to become a novel target for the treatment of adipose tissue fibrosis.

关 键 词：ORM adipose tissue FIBROSIS AMPK TGF-β1 3T3-L1 fibroblasts dorsomorphin obesity metabolic disorders 

分 类 号：R965[医药卫生—药理学]