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The adipokine orosomucoid alleviates adipose tissue fibrosis via the AMPK pathway

Abstract

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.

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Fig. 1: ORM1-deficient mice exhibit an obese phenotype with adiposity and excessive collagen deposition.
Fig. 2: ORM1 deficiency increases the expression of ECM regulators involved in adipose tissue fibrosis.
Fig. 3: ORM administration ameliorates the abnormal synthesis and degradation of ECM components in the iWAT of HFD mice.
Fig. 4: ORM administration ameliorates the abnormal synthesis and degradation of ECM components in the iWAT of db/db mice.
Fig. 5: ORM stimulates AMPK activity and inhibits TGF-β1 signaling in the iWAT of obese mice.
Fig. 6: AMPK mediates the antifibrotic effect of ORM in vitro.
Fig. 7: Proposed mechanism by which ORM is involved in adipose tissue fibrosis.

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Acknowledgements

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), and the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program, China (No. 2018ZX09711002-003-015).

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Authors

Contributions

XL, YS, and PYW designed the study. XL, YS, and WDZ supervised the experiments. PYW and JYF carried out most of the experiments. ZZ, ZQ, YC, XMD, and BHH helped with some of the experiments. JW bred and maintained the ORM1-deficient mice. All authors analyzed and interpreted the experimental data. PYW and YS drafted the graphs and wrote the manuscript. XL revised the manuscript. ZZ and ZQ proofread and revised the manuscript.

Corresponding authors

Correspondence to Wei-dong Zhang or Yang Sun or Xia Liu.

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The authors declare no competing interests.

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Cite this article

Wang, Py., Feng, Jy., Zhang, Z. et al. The adipokine orosomucoid alleviates adipose tissue fibrosis via the AMPK pathway. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00666-9

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Keywords

  • ORM
  • adipose tissue
  • fibrosis
  • AMPK
  • TGF-β1
  • 3T3-L1 fibroblasts
  • dorsomorphin
  • obesity
  • metabolic disorders

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