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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Buechler C, Krautbauer S, Eisinger K. Adipose tissue fibrosis. World J Diabetes. 2015;6:548–53.
Chun TH. Peri-adipocyte ECM remodeling in obesity and adipose tissue fibrosis. Adipocyte. 2012;1:89–95.
Karsdal MA, Nielsen SH, Leeming DJ, Langholm LL, Nielsen MJ, Manon-Jensen T, et al. The good and the bad collagens of fibrosis—their role in signaling and organ function. Adv Drug Deliv Rev. 2017;121:43–56.
Guglielmi V, Cardellini M, Cinti F, Corgosinho F, Cardolini I, D’Adamo M, et al. Omental adipose tissue fibrosis and insulin resistance in severe obesity. Nutr Diabetes. 2015;5:e175.
Datta R, Podolsky MJ, Atabai K. Fat fibrosis: friend or foe? JCI Insight. 2018;3:e122289.
Lin D, Chun TH, Kang L. Adipose extracellular matrix remodelling in obesity and insulin resistance. Biochem Pharmacol. 2016;119:8–16.
Sun K, Tordjman J, Clément K, Scherer PE. Fibrosis and adipose tissue dysfunction. Cell Metab. 2013;18:470–77.
Luo T, Nocon A, Fry J, Sherban A, Rui X, Jiang B, et al. AMPK activation by metformin suppresses abnormal extracellular matrix remodeling in adipose tissue and ameliorates insulin resistance in obesity. Diabetes. 2016;65:2295–310.
Hasegawa Y, Ikeda K, Chen Y, Alba DL, Stifler D, Shinoda K, et al. Repression of adipose tissue fibrosis through a PRDM16-GTF2IRD1 complex improves systemic glucose homeostasis. Cell Metab. 2018;27:180–94.
Kawanishi N, Niihara H, Mizokami T, Yano H, Suzuki K. Exercise training attenuates adipose tissue fibrosis in diet-induced obese mice. Biochem Biophys Res Commun. 2013;440:774–9.
Fournier T, Medjoubi-N N, Porquet D. Alpha-1-acid glycoprotein. Biochim Biophys Acta. 2000;1482:157–71.
Luo Z, Lei H, Sun Y, Liu X, Su DF. Orosomucoid, an acute response protein with multiple modulating activities. J Physiol Biochem. 2015;71:329–40.
Lee YS, Choi JW, Hwang I, Lee JW, Lee JH, Kim AY, et al. Adipocytokine orosomucoid integrates inflammatory and metabolic signals to preserve energy homeostasis by resolving immoderate inflammation. J Biol Chem. 2010;285:22174–85.
Alfadda AA, Fatma S, Chishti MA, Al-Naami MY, Elawad R, Mendoza CD, et al. Orosomucoid serum concentrations and fat depot-specific mRNA and protein expression in humans. Mol Cells. 2012;33:35–41.
Sun Y, Yang Y, Qin Z, Cai J, Guo X, Tang Y, et al. The acute-phase protein orosomucoid regulates food intake and energy homeostasis via leptin receptor signaling pathway. Diabetes. 2016;65:1630–41.
Lei H, Sun Y, Luo Z, Yourek G, Gui H, Yang Y, et al. Fatigue-induced orosomucoid 1 acts on C-C chemokine receptor type 5 to enhance muscle endurance. Sci Rep. 2016;6:18839.
Dai B, Huang S, Deng Y. Modified insoluble dietary fibers in okara affect body composition, serum metabolic properties, and fatty acid profiles in mice fed high-fat diets: an NMR investigation. Food Res Int. 2019;116:1239–46.
Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170:1807–16.
Khan T, Muise ES, Iyengar P, Wang ZV, Chandalia M, Abate N, et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol. 2009;29:1575–91.
Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12:325–38.
Kim H, Moon SY, Kim JS, Baek CH, Kim M, Min JY, et al. Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis. Am J Physiol Ren Physiol. 2015;308:226–36.
Satriano J, Sharma K, Blantz RC, Deng A. Induction of AMPK activity corrects early pathophysiological alterations in the subtotal nephrectomy model of chronic kidney disease. Am J Physiol Ren Physiol. 2013;305:727–33.
Wang Y, Jia L, Hu Z, Entman ML, Mitch WE, Wang Y. AMP-activated protein kinase/myocardin-related transcription factor—a signaling regulates fibroblast activation and renal fibrosis. Kidney Int. 2018;93:81–94.
Qi H, Liu Y, Li S, Chen Y, Li L, Cao Y, et al. Activation of AMPK attenuated cardiac fibrosis by inhibiting CDK2 via p21/p27 and miR-29 family pathways in rats. Mol Ther Nucleic Acids. 2017;8:277–90.
Mishra R, Cool BL, Laderoute KR, Foretz M, Viollet B, Simonson MS. AMP-activated protein kinase inhibits transforming growth factor-beta-induced Smad3-dependent transcription and myofibroblast transdifferentiation. J Biol Chem. 2008;283:10461–9.
Li NS, Zou JR, Lin H, Ke R, He XL, Xiao L, et al. LKB1/AMPK inhibits TGF-beta1 production and the TGF-beta signaling pathway in breast cancer cells. Tumour Biol. 2016;37:8249–58.
Thakur S, Viswanadhapalli S, Kopp JB, Shi Q, Barnes JL, Block K, et al. Activation of AMP-activated protein kinase prevents TGF-beta1-induced epithelial-mesenchymal transition and myofibroblast activation. Am J Pathol. 2015;185:2168–80.
Qin Z, Wan JJ, Sun Y, Wang PY, Su DF, Lei H, et al. ORM promotes skeletal muscle glycogen accumulation via CCR5-activated AMPK pathway in mice. Front Pharmacol. 2016;7:302.
Komori H, Nishi K, Uehara N, Watanabe H, Shuto T, Suenaga A, et al. Characterization of hepatic cellular uptake of alpha1-acid glycoprotein (AGP), part 2: involvement of hemoglobin beta-chain on plasma membranes in the uptake of human AGP by liver parenchymal cells. J Pharm Sci. 2012;101:1607–15.
Atemezem A, Mbemba E, Vassy R, Slimani H, Saffar L, Gattegno L. Human alpha1-acid glycoprotein binds to CCR5 expressed on the plasma membrane of human primary macrophages. Biochem J. 2001;356:121–8.
Gunnarsson P, Levander L, Påhlsson P, Grenegård M. The acute-phase protein alpha 1-acid glycoprotein (AGP) induces rises in cytosolic Ca2+ in neutrophil granulocytes via sialic acid binding immunoglobulin-like lectins (siglecs). FASEB J. 2007;21:4059–69.
Nagase H, Woessner JF Jr. Matrix metalloproteinases. J Biol Chem. 1999;274:21491–4.
Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta. 2010;1803:55–71.
Roeb E. Matrix metalloproteinases and liver fibrosis (translational aspects). Matrix Biol. 2018;68-69:463–73.
Akama T, Chun TH. Transcription factor 21 (TCF21) promotes proinflammatory interleukin 6 expression and extracellular matrix remodeling in visceral adipose stem cells. J Biol Chem. 2018;293:6603–10.
Divoux A, Tordjman J, Lacasa D, Veyrie N, Hugol D, Aissat A, et al. Fibrosis in human adipose tissue: composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes. 2010;59:2817–25.
Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3:349–63.
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).
The authors declare no competing interests.
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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
- adipose tissue
- 3T3-L1 fibroblasts
- metabolic disorders