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Involvement of the secreted protein Metrnl in human diseases

Abstract

Metrnl, a secreted protein expressed in white adipose tissue, has been identified as a novel adipokine. It is also highly expressed in barrier tissues, including the skin, intestinal and respiratory tract epithelium in both mice and humans. Research shows that its expression is upregulated by inflammation, chronic high-fat diets, exercise, cold exposure, etc., and it plays important roles in promoting neurite extension, enhancing white fat browning, improving insulin sensitivity, modulating lipid metabolism and regulating inflammatory response, the latter implying Metrnl is a new cytokine. These studies suggest that Metrnl could be a promising biomarker and a potential therapeutic target for the related diseases. For proving this, clinical studies need to be performed to bridge the gap between bench and bedside. In this paper, we summarize the progress in recent clinical research on Metrnl. Most of these clinical studies are designed to confirm the relationship between circulating Metrnl and metabolic or cardiovascular disease (type 2 diabetes and coronary heart disease), or immune inflammation-related diseases, such as colitis, psoriasis and arthritis. Although blood Metrnl seems to fluctuate and are affected by many factors, such as drugs, physical exercise, and cold exposure, these clinical studies provide reliable clues that Metrnl is associated with coronary heart disease, inflammation-related diseases, etc. Nevertheless, the roles of Metrnl in some diseases such as nervous system diseases remain unclear, and its putative involvement should be further clarified. These studies could promote the application of Metrnl in clinic as a new therapeutic target.

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Fig. 1: Metrnl regulates the intracellular signaling pathway.
Fig. 2: The functions of Metrnl found by laboratory research and their corresponding clinical diseases.

References

  1. 1.

    Fasshauer M, Bluher M. Adipokines in health and disease. Trends Pharmacol Sci. 2015;36:461–70.

    CAS  Article  Google Scholar 

  2. 2.

    Li ZY, Zheng SL, Wang P, Xu TY, Guan YF, Zhang YJ, et al. Subfatin is a novel adipokine and unlike meteorin in adipose and brain expression. CNS Neurosci Ther. 2014;20:344–54.

    CAS  Article  Google Scholar 

  3. 3.

    Ushach I, Burkhardt AM, Martinez C, Hevezi PA, Gerber PA, Buhren BA, et al. METEORIN-LIKE is a cytokine associated with barrier tissues and alternatively activated macrophages. Clin Immunol. 2015;156:119–27.

    CAS  Article  Google Scholar 

  4. 4.

    Li ZY, Fan MB, Zhang SL, Qu Y, Zheng SL, Song J, et al. Intestinal metrnl released into the gut lumen acts as a local regulator for gut antimicrobial peptides. Acta Pharmacol Sin. 2016;37:1458–66.

    Article  Google Scholar 

  5. 5.

    Jorgensen JR, Fransson A, Fjord-Larsen L, Thompson LH, Houchins JP, Andrade N, et al. Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo. Exp Neurol. 2012;233:172–81.

    CAS  Article  Google Scholar 

  6. 6.

    Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell. 2014;157:1279–91.

    CAS  Article  Google Scholar 

  7. 7.

    Li ZY, Song J, Zheng SL, Fan MB, Guan YF, Qu Y, et al. Adipocyte metrnl antagonizes insulin resistance through PPARgamma signaling. Diabetes. 2015;64:4011–22.

    CAS  Article  Google Scholar 

  8. 8.

    Qi Q, Hu WJ, Zheng SL, Zhang SL, Le YY, Li ZY, et al. Metrnl deficiency decreases blood HDL cholesterol and increases blood triglyceride. Acta Pharmacol Sin. 2020. https://doi.org/10.1038/s41401-020-0368-8.

  9. 9.

    Zheng SL, Li ZY, Song J, Liu JM, Miao CY. Metrnl: a secreted protein with new emerging functions. Acta Pharmacol Sin. 2016;37:571–9.

    CAS  Article  Google Scholar 

  10. 10.

    Ushach I, Arrevillaga-Boni G, Heller GN, Pone E, Hernandez-Ruiz M, Catalan-Dibene J, et al. Meteorin-like/Meteorin-beta Is a novel immunoregulatory cytokine associated with inflammation. J Immunol. 2018;201:3669–76.

    CAS  Article  Google Scholar 

  11. 11.

    Wang K, Li F, Wang C, Deng Y, Cao Z, Cui Y, et al. Serum levels of Meteorin-Like (Metrnl) are increased in patients with newly diagnosed type 2 diabetes mellitus and are associated with insulin resistance. Med Sci Monit. 2019;25:2337–43.

    CAS  Article  Google Scholar 

  12. 12.

    Lappas M. Maternal obesity and gestational diabetes decrease metrnl concentrations in cord plasma. J Matern Fetal Neonatal Med. 2019:1–5. https://doi.org/10.1080/14767058.2019.1676713.

  13. 13.

    Chung HS, Hwang SY, Choi JH, Lee HJ, Kim NH, Yoo HJ, et al. Implications of circulating Meteorin-like (Metrnl) level in human subjects with type 2 diabetes. Diabetes Res Clin Pr. 2018;136:100–7.

    CAS  Article  Google Scholar 

  14. 14.

    Dadmanesh M, Aghajani H, Fadaei R, Ghorban K. Lower serum levels of Meteorin-like/Subfatin in patients with coronary artery disease and type 2 diabetes mellitus are negatively associated with insulin resistance and inflammatory cytokines. PLoS One. 2018;13:e0204180.

    Article  Google Scholar 

  15. 15.

    Liu ZX, Ji HH, Yao MP, Wang L, Wang Y, Zhou P, et al. Serum Metrnl is associated with the presence and severity of coronary artery disease. J Cell Mol Med. 2019;23:271–80.

    CAS  Article  Google Scholar 

  16. 16.

    Zuo L, Ge S, Ge Y, Li J, Zhu B, Zhang Z, et al. The Adipokine Metrnl ameliorates chronic colitis in Il-10-/- mice by attenuating mesenteric adipose tissue lesions during spontaneous colitis. J Crohns Colitis. 2019;13:931–41.

    Article  Google Scholar 

  17. 17.

    Bridgewood C, Russell T, Weedon H, Baboolal T, Watad A, Sharif K, et al. The novel cytokine Metrnl/IL-41 is elevated in psoriatic arthritis synovium and inducible from both entheseal and synovial fibroblasts. Clin Immunol. 2019;208:108253.

    CAS  Article  Google Scholar 

  18. 18.

    Miao CY. Introduction: Adipokines and cardiovascular disease. Clin Exp Pharmacol Physiol. 2011;38:860–3.

    CAS  Article  Google Scholar 

  19. 19.

    Zhu X, Zhang HW, Chen HN, Deng XJ, Tu YX, Jackson AO, et al. Perivascular adipose tissue dysfunction aggravates adventitial remodeling in obese mini pigs via NLRP3 inflammasome/IL-1 signaling pathway. Acta Pharmacol Sin. 2019;40:46–54.

    CAS  Article  Google Scholar 

  20. 20.

    AlKhairi I, Cherian P, Abu-Farha M, Madhoun AA, Nizam R, Melhem M, et al. Increased expression of Meteorin-Like hormone in type 2 diabetes and obesity and its association with irisin. Cells. 2019;8:1283.

    CAS  Article  Google Scholar 

  21. 21.

    Lee JH, Kang YE, Kim JM, Choung S, Joung KH, Kim HJ, et al. Serum Meteorin-like protein levels decreased in patients newly diagnosed with type 2 diabetes. Diabetes Res Clin Pract. 2018;135:7–10.

    CAS  Article  Google Scholar 

  22. 22.

    Zheng SL, Li ZY, Zhang Z, Wang DS, Xu J, Miao CY. Evaluation of two commercial enzyme-linked immunosorbent assay kits for the detection of human circulating Metrnl. Chem Pharm Bull (Tokyo). 2018;66:391–8.

    CAS  Article  Google Scholar 

  23. 23.

    El-Ashmawy HM, Selim FO, Hosny TAM, Almassry HN. Association of low serum Meteorin like (Metrnl) concentrations with worsening of glucose tolerance, impaired endothelial function and atherosclerosis. Diabetes Res Clin Pract. 2019;150:57–63.

    CAS  Article  Google Scholar 

  24. 24.

    Eaton M, Granata C, Barry J, Safdar A, Bishop D, Little JP. Impact of a single bout of high-intensity interval exercise and short-term interval training on interleukin-6, FNDC5, and METRNL mRNA expression in human skeletal muscle. J Sport Health Sci. 2018;7:191–6.

    Article  Google Scholar 

  25. 25.

    Saghebjoo M, Einaloo A, Mogharnasi M, Ahmadabadi F. The response of meteorin-like hormone and interleukin-4 in overweight women during exercise in temperate, warm and cold water. Horm Mol Biol Clin Investig. 2018;36:/j/hmbci.2018.36.issue-3/hmbci-2018-0027/hmbci-2018-0027.xml.

  26. 26.

    Loffler D, Landgraf K, Rockstroh D, Schwartze JT, Dunzendorfer H, Kiess W, et al. METRNL decreases during adipogenesis and inhibits adipocyte differentiation leading to adipocyte hypertrophy in humans. Int J Obes (Lond). 2017;41:112–9.

    CAS  Article  Google Scholar 

  27. 27.

    Wang C, Pan Y, Song J, Sun Y, Li H, Chen L, et al. Serum Metrnl level is correlated with insulin resistance, but not with beta-cell function in type 2 diabetics. Med Sci Monit. 2019;25:8968–74.

    CAS  Article  Google Scholar 

  28. 28.

    Pellitero S, Piquer-Garcia I, Ferrer-Curriu G, Puig R, Martinez E, Moreno P, et al. Opposite changes in meteorin-like and oncostatin m levels are associated with metabolic improvements after bariatric surgery. Int J Obes (Lond). 2018;42:919–22.

    CAS  Article  Google Scholar 

  29. 29.

    Du Y, Ye X, Lu A, Zhao D, Liu J, Cheng J, et al. Inverse relationship between serum Metrnl levels and visceral fat obesity (VFO) in patients with type 2 diabetes. Diabetes Res Clin Pr. 2020;161:108068.

    CAS  Article  Google Scholar 

  30. 30.

    Fouani FZ, Fadaei R, Moradi N, Zandieh Z, Ansaripour S, Yekaninejad MS, et al. Circulating levels of Meteorin-like protein in polycystic ovary syndrome: a case-control study. PLoS One. 2020;15:e0231943.

    CAS  Article  Google Scholar 

  31. 31.

    Knapp M, Tu X, Wu R. Vascular endothelial dysfunction, a major mediator in diabetic cardiomyopathy. Acta Pharmacol Sin. 2019;40:1–8.

    CAS  Article  Google Scholar 

  32. 32.

    Li ZY, Wang P, Miao CY. Adipokines in inflammation, insulin resistance and cardiovascular disease. Clin Exp Pharmacol Physiol. 2011;38:888–96.

    CAS  Article  Google Scholar 

  33. 33.

    Zhang SL, Li ZY, Wang DS, Xu TY, Fan MB, Cheng MH, et al. Aggravated ulcerative colitis caused by intestinal Metrnl deficiency is associated with reduced autophagy in epithelial cells. Acta Pharmacol Sin. 2020;41:763–70.

    CAS  Article  Google Scholar 

  34. 34.

    Gong W, Liu Y, Wu Z, Wang S, Qiu G, Lin S. Meteorin-like shows unique expression pattern in bone and its overexpression inhibits osteoblast differentiation. PLoS One. 2016;11:e0164446.

    Article  Google Scholar 

  35. 35.

    Watad A, Cuthbert RJ, Amital H, McGonagle D. Enthesitis: much more than focal insertion point inflammation. Curr Rheumatol Rep. 2018;20:41.

    Article  Google Scholar 

  36. 36.

    Nishino J, Yamashita K, Hashiguchi H, Fujii H, Shimazaki T, Hamada H. Meteorin: a secreted protein that regulates glial cell differentiation and promotes axonal extension. EMBO J. 2004;23:1998–2008.

    CAS  Article  Google Scholar 

  37. 37.

    Lee HS, Han J, Lee SH, Park JA, Kim KW. Meteorin promotes the formation of GFAP-positive glia via activation of the Jak-STAT3 pathway. J Cell Sci. 2010;123:1959–68.

    CAS  Article  Google Scholar 

  38. 38.

    Baht GS, Bareja A, Lee DE, Rao RR, Huang R, Huebner JL, et al. Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1 mechanism. Nat Metab. 2020;2:278–89.

    CAS  Article  Google Scholar 

  39. 39.

    Lee JO, Byun WS, Kang MJ, Han JA, Moon J, Shin MJ, et al. The myokine meteorin-like (metrnl) improves glucose tolerance in both skeletal muscle cells and mice by targeting AMPKalpha2. FEBS J. 2020;287:2087–104.

    CAS  Article  Google Scholar 

  40. 40.

    Jung TW, Lee SH, Kim HC, Bang JS, Abd El-Aty AM, Hacimuftuoglu A, et al. METRNL attenuates lipid-induced inflammation and insulin resistance via AMPK or PPARdelta-dependent pathways in skeletal muscle of mice. Exp Mol Med. 2018;50:122.

    Article  Google Scholar 

  41. 41.

    Surace C, Piazzolla S, Sirleto P, Digilio MC, Roberti MC, Lombardo A, et al. Mild ring 17 syndrome shares common phenotypic features irrespective of the chromosomal breakpoints location. Clin Genet. 2009;76:256–62.

    CAS  Article  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China Major Project (No. 81730098), the Medical Innovation Project (No. 16QNP087), and the Shanghai Science and Technology Commission Project (No. 16JC1405100 and No. 201409004600).

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Correspondence to Zhi-yong Li or Chao-yu Miao.

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Miao, Zw., Hu, Wj., Li, Zy. et al. Involvement of the secreted protein Metrnl in human diseases. Acta Pharmacol Sin 41, 1525–1530 (2020). https://doi.org/10.1038/s41401-020-00529-9

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Keywords

  • secreted protein
  • adipokine
  • Metrnl
  • type 2 diabetes
  • obesity
  • coronary heart disease
  • atherosclerosis
  • colitis
  • psoriasis
  • arthritis

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