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MiR-143-3p/FNDC5 axis: a novel regulator of insulin sensitivity

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Abstract

Purpose

Insulin resistance is a key hallmark in type 2 diabetes. In recent decades, there have been numerous studies of the causes of insulin resistance. microRNAs (miRNAs) participate in the regulation of multiple aspects of energy metabolism and miR-143-3p has been shown to induce insulin resistance. We aimed to predict the downstream targets of miR-143-3p and found a miR-143-3p binding site on the 3′-untranslated region of FNDC5 (Fibronectin type III domain containing 5) mRNA.

Methods

We first confirmed that FNDC5 mRNA is a target of miR-143-3p using a double luciferase experiment, then constructed a prokaryotic expression system for the mature form of FNDC5, irisin, and expressed and purified irisin protein. We transfected a miR-143-3p mimic into HepG2-NTCP (Na+-taurocholate cotransporting polypeptide) cells using an NTCP targeting vector, then 24 h later, the glucose concentration of the culture medium, western blot analysis was analyzed. We next co-incubated the cells transfected with the miR-143-3p mimic with irisin for 12 h following by the assay of glucose uptake and AKT phosphorylation.

Results

The glucose concentration of the culture medium was higher than that associated with control miRNA-transfected cells (p < 0.01). Western blot analysis showed that the miR-143-3p mimic significantly reduced the expression of FNDC5 (p < 0.05) and the phosphorylation of AKT (Protein kinase B) (p < 0.05), implying impaired insulin signaling. which increased the glucose uptake (p < 0.0001) and AKT phosphorylation in the cells (p < 0.05).

Conclusion

We conclude that FNDC5 is a direct target of miR-143-3p and that miR-143-3p induces insulin resistance by reducing its expression.

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References

  1. A.G. Tabák, C. Herder, W. Rathmann, E.J. Brunner, M. Kivimäki, Prediabetes: a high-risk state for diabetes development. Lancet 379, 2279–2290 (2012)

    Article  PubMed  PubMed Central  Google Scholar 

  2. J.Y. Kim, F. Bacha, H. Tfayli, S.F. Michaliszyn, S. Yousuf, S. Arslanian, Adipose tissue insulin resistance in youth on the spectrum from normal weight to obese and from normal glucose tolerance to impaired glucose tolerance to type 2 diabetes. Diabetes Care 42, 265–272 (2019)

    Article  CAS  PubMed  Google Scholar 

  3. A. Yassin, A. Haider, K.S. Haider, M. Caliber, G. Doros, F. Saad, W.T. Garvey, Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes: eight-year data from a registry study. Diabetes Care 42, 1104–1111 (2019)

    Article  CAS  PubMed  Google Scholar 

  4. O.A. Kent, M.N. McCall, T.C. Cornish, M.K. Halushka, Lessons from miR-143/145: the importance of cell-type localization of miRNAs. Nucleic Acids Res. 42, 7528–7538 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. L. Xihua, T. Shengjie, G. Weiwei, E. Matro, T. Tingting, L. Lin, W. Fang, Z. Jiaqiang, Z. Fenping, L. Hong, Circulating miR-143-3p inhibition protects against insulin resistance in metabolic syndrome via targeting of the insulin-like growth factor 2 receptor. Transl. Res. 205, 33–43 (2019)

    Article  PubMed  Google Scholar 

  6. X. Lin, Y. Du, W. Lu, W. Gui, S. Sun, Y. Zhu, G. Wang, D.T. Eserberg, F. Zheng, J. Zhou, F. Wu, H. Li, CircRNF111 protects against insulin resistance and lipid deposition via regulating miR-143-3p/IGF2R axis in metabolic syndrome. Front. Cell Dev. Biol. 9, 663148 (2021)

    Article  PubMed  PubMed Central  Google Scholar 

  7. X. An, K. Ma, Z. Zhang, T. Zhao, X. Zhang, B. Tang, Z. Li, miR-17, miR-21, and miR-143 enhance adipogenic differentiation from porcine bone marrow-derived mesenchymal stem cells. DNA Cell Biol. 35, 410–416 (2016)

    Article  CAS  PubMed  Google Scholar 

  8. T. de Oliveira Silva, C.A. Lino, J.B. Miranda, C.S. Balbino-Silva, G. Lunardon, V.M. Lima, L. Jensen, J. Donato Jr, M.C. Irigoyen, M.L.M. Barreto-Chaves, The miRNA-143-3p–Sox6–Myh7 pathway is altered in obesogenic diet‐induced cardiac hypertrophy. Exp. Physiol. 107, 892–905 (2022)

    Article  PubMed  Google Scholar 

  9. S.D. Jordan, M. Krüger, D.M. Willmes, N. Redemann, F.T. Wunderlich, H.S. Brönneke, C. Merkwirth, H. Kashkar, V.M. Olkkonen, T. Böttger, Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nat. Cell Biol. 13, 434–446 (2011)

    Article  CAS  PubMed  Google Scholar 

  10. K.W. Taroeno-Hariadi, M.S. Hardianti, H. Sinorita, T. Aryandono, Obesity, leptin, and deregulation of microRNA in lipid metabolisms: their contribution to breast cancer prognosis. Diabetol. Metab. Syndr. 13, 10 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. P. Gonzalez-Lopez, C. Ares-Carral, A.R. Lopez-Pastor, J. Infante-Menendez, T. Gonzalez Illaness, M. Vega de Ceniga, L. Esparza, N. Beneit, J.L. Martin-Ventura, O. Escribano, A. Gomez-Hernandez, Implication of miR-155-5p and miR-143-3p in the vascular insulin resistance and instability of human and experimental atherosclerotic plaque. Int. J. Mol. Sci. 23, 10253 (2022)

  12. S. Mu, B. Kang, W. Zeng, Y. Sun, F. Yang, MicroRNA-143-3p inhibits hyperplastic scar formation by targeting connective tissue growth factor CTGF/CCN2 via the Akt/mTOR pathway. Mol. Cell Biochem. 416, 99–108 (2016)

    Article  CAS  PubMed  Google Scholar 

  13. H.K. Al-Hakeim, Q.J. Al-Kaabi, M. Maes, High mobility group box 1 and Dickkopf-related protein 1 as biomarkers of glucose toxicity, atherogenicity, and lower β cell function in patients with type 2 diabetes mellitus. Growth Factors 40, 240–253 (2022)

    Article  CAS  PubMed  Google Scholar 

  14. G.I. Smith, M. Shankaran, M. Yoshino, G.G. Schweitzer, M. Chondronikola, J.W. Beals, A.L. Okunade, B.W. Patterson, E. Nyangau, T. Field, Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J. Clin. Investig. 130, 1453–1460 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. X. Ding, T. Jian, Y. Wu, Y. Zuo, J. Li, H. Lv, L. Ma, B. Ren, L. Zhao, W. Li, Ellagic acid ameliorates oxidative stress and insulin resistance in high glucose-treated HepG2 cells via miR-223/keap1-Nrf2 pathway. Biomed. Pharmacother. 110, 85–94 (2019)

    Article  CAS  PubMed  Google Scholar 

  16. J.C. Jonas, A. Sharma, W. Hasenkamp, H. Ilkova, G. Patane, R. Laybutt, S. Bonner-Weir, G.C. Weir, Chronic hyperglycemia triggers loss of pancreatic beta cell differentiation in an animal model of diabetes. J. Biol. Chem. 274, 14112–14121 (1999)

    Article  CAS  PubMed  Google Scholar 

  17. D. Albanes, S.J. Weinstein, M.E. Wright, S. Männistö, P.J. Limburg, K. Snyder, J. Virtamo, Serum insulin, glucose, indices of insulin resistance, and risk of prostate cancer. J. Natl Cancer Inst. 101, 1272–1279 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. D.E. James, J. Stöckli, M.J. Birnbaum, The aetiology and molecular landscape of insulin resistance. Nat. Rev. Mol. Cell Biol. 22, 751–771 (2021)

    Article  CAS  PubMed  Google Scholar 

  19. F.C. Sasso, P.C. Pafundi, R. Marfella, P. Calabrò, F. Piscione, F. Furbatto, G. Esposito, R. Galiero, F. Gragnano, L. Rinaldi, Adiponectin and insulin resistance are related to restenosis and overall new PCI in subjects with normal glucose tolerance: the prospective AIRE Study. Cardiovasc. Diabetol. 18, 1–13 (2019)

    Article  Google Scholar 

  20. P. Boström, J. Wu, M.P. Jedrychowski, A. Korde, L. Ye, J.C. Lo, K.A. Rasbach, E.A. Boström, J.H. Choi, J.Z. Long, A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012)

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  21. A. Icli, E. Cure, M. Cumhur Cure, A.U. Uslu, S. Balta, S. Arslan, D. Sakiz, A. Kucuk, Novel myokine: irisin may be an independent predictor for subclinic atherosclerosis in Behçet’s disease. J. Investig. Med. 64, 875–881 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  22. R. Zhang, T. Fu, X. Zhao, Y. Qiu, X. Hu, H. Shi, X. Yin, Association of circulating irisin levels with adiposity and glucose metabolic profiles in a middle-aged chinese population: a cross-sectional study. Diabetes Metab. Syndr. Obes. Targets Ther. 13, 4105 (2020)

    Article  CAS  Google Scholar 

  23. N. Perakakis, G.A. Triantafyllou, J.M. Fernández-Real, J.Y. Huh, K.H. Park, J. Seufert, C.S. Mantzoros, Physiology and role of irisin in glucose homeostasis. Nat. Rev. Endocrinol. 13, 324–337 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. L. Gao, J. Yang, J. Feng, Z. Liu, Y. Dong, J. Luo, L. Yu, J. Wang, H. Fan, W. Ma, PreS/2-21-guided siRNA nanoparticles target to inhibit hepatitis B virus infection and replication. Front. Immunol. 13, 856463 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Y.-J. Zhou, N. Xu, X.-C. Zhang, Y.-Y. Zhu, S.-W. Liu, Y.-N. Chang, Chrysin improves glucose and lipid metabolism disorders by regulating the AMPK/PI3K/AKT signaling pathway in insulin-resistant HepG2 cells and HFD/STZ-induced C57BL/6J mice. J. Agric. Food Chem. 69, 5618–5627 (2021)

    Article  CAS  PubMed  Google Scholar 

  26. J. Zhu, C. Yu, H. Zhou, X. Wei, Y. Wang, Comparative evaluation for phytochemical composition and regulation of blood glucose, hepatic oxidative stress and insulin resistance in mice and HepG2 models of four typical Chinese dark teas. J. Sci. Food Agric. 101, 6563–6577 (2021)

    Article  CAS  PubMed  Google Scholar 

  27. R. Alaaeldin, I.A. Abdel-Rahman, H.A. Hassan, N. Youssef, A.E. Allam, S.F. Abdelwahab, Q.-L. Zhao, M. Fathy, Carpachromene ameliorates insulin resistance in HepG2 cells via modulating IR/IRS1/PI3k/Akt/GSK3/FoxO1 pathway. Molecules 26, 7629 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. X. Ding, T. Jian, Y. Wu, Y. Zuo, J. Li, H. Lv, L. Ma, B. Ren, L. Zhao, W. Li, J. Chen, Ellagic acid ameliorates oxidative stress and insulin resistance in high glucose-treated HepG2 cells via miR-223/keap1-Nrf2 pathway. Biomed. Pharmacother. 110, 85–94 (2019)

    Article  CAS  PubMed  Google Scholar 

  29. A. König, J. Yang, E. Jo, K.H.P. Park, H. Kim, T.T. Than, X. Song, X. Qi, X. Dai, S. Park, Efficient long-term amplification of hepatitis B virus isolates after infection of slow proliferating HepG2-NTCP cells. J. Hepatol. 71, 289–300 (2019)

    Article  PubMed  Google Scholar 

  30. M.J. De Rosa, T. Veuthey, J. Florman, J. Grant, M.G. Blanco, N. Andersen, J. Donnelly, D. Rayes, M.J. Alkema, The flight response impairs cytoprotective mechanisms by activating the insulin pathway. Nature 573, 135–138 (2019)

    Article  ADS  PubMed  Google Scholar 

  31. Y. Nishida, A. Nawaz, T. Kado, A. Takikawa, Y. Igarashi, Y. Onogi, T. Wada, T. Sasaoka, S. Yamamoto, M. Sasahara, Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway. J. Cachexia Sarcopenia Muscle 11, 241–258 (2020)

    Article  PubMed  PubMed Central  Google Scholar 

  32. D. Kellar, S. Craft, Brain insulin resistance in Alzheimer’s disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol. 19, 758–766 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. H. Wu, C.M. Ballantyne, Metabolic inflammation and insulin resistance in obesity. Circ. Res. 126, 1549–1564 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. A. Di Pino, R.A. DeFronzo, Insulin resistance and atherosclerosis: implications for insulin-sensitizing agents. Endocr. Rev. 40, 1447–1467 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  35. M.J. Watt, P.M. Miotto, W. De Nardo, M.K. Montgomery, The liver as an endocrine organ—linking NAFLD and insulin resistance. Endocr. Rev. 40, 1367–1393 (2019)

    Article  PubMed  Google Scholar 

  36. R.S. Khan, F. Bril, K. Cusi, P.N. Newsome, Modulation of insulin resistance in nonalcoholic fatty liver disease. Hepatology 70, 711–724 (2019)

    Article  CAS  PubMed  Google Scholar 

  37. L.A. Broadfield, J.A.G. Duarte, R. Schmieder, D. Broekaert, K. Veys, M. Planque, K. Vriens, Y. Karasawa, F. Napolitano, S. Fujita, Fat induces glucose metabolism in nontransformed liver cells and promotes liver tumorigenesis fat induces glucose metabolization. Cancer Res. 81, 1988–2001 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. D. Sekar, J. Johnson, M. Biruntha, G. Lakhmanan, D. Gurunathan, K. Ross, Biological and clinical relevance of microRNAs in mitochondrial diseases/dysfunctions. DNA Cell Biol. 39, 1379–1384 (2020)

    Article  CAS  PubMed  Google Scholar 

  39. P. Agbu, R.W. Carthew, MicroRNA-mediated regulation of glucose and lipid metabolism. Nat. Rev. Mol. Cell Biol. 22, 425–438 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. B. Wang, Y. Xu, Y. Wei, L. Lv, N. Liu, R. Lin, X. Wang, B. Shi, Human mesenchymal stem cell-derived exosomal microRNA-143 promotes apoptosis and suppresses cell growth in pancreatic cancer via target gene regulation. Front. Genet. 12, 581694 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. B.R. Ely, Z.S. Clayton, C.E. McCurdy, J. Pfeiffer, K.W. Needham, L.N. Comrada, C.T. Minson, Heat therapy improves glucose tolerance and adipose tissue insulin signaling in polycystic ovary syndrome. Am. J. Physiol. Endocrinol. Metab. 317, E172–E182 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. H. Yan, C. Opachaloemphan, F. Carmona-Aldana, G. Mancini, J. Mlejnek, N. Descostes, B. Sieriebriennikov, A. Leibholz, X. Zhou, L. Ding, Insulin signaling in the long-lived reproductive caste of ants. Science 377, 1092–1099 (2022)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  43. S.I. Dreher, S. Hockele, P. Huypens, M. Irmler, C. Hoffmann, T. Jeske, M. Hastreiter, A. Moller, A.L. Birkenfeld, H.U. Haring, A. Peter, J. Beckers, M. Hrabe de Angelis, C. Weigert, TGF-beta induction of miR-143/145 is associated to exercise response by influencing differentiation and insulin signaling molecules in human skeletal muscle. Cells 10, 3443 (2021)

  44. J. Vogel, D. Niederer, T. Engeroff, L. Vogt, C. Troidl, T. Schmitz-Rixen, W. Banzer, K. Troidl, Effects on the profile of circulating miRNAs after single bouts of resistance training with and without blood flow restriction—a three-arm, randomized crossover trial. Int. J. Mol. Sci. 20, 3249 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. L.M. Margolis, S.J. Lessard, Y. Ezzyat, R.A. Fielding, D.A. Rivas, Circulating microRNA are predictive of aging and acute adaptive response to resistance exercise in men. J. Gerontol. Ser. A Biomed. Sci. Med. Sci. 72, 1319–1326 (2017)

    CAS  Google Scholar 

  46. M. Daneshi-Maskooni, S.A. Keshavarz, M. Qorbani, S. Mansouri, S.M. Alavian, M. Badri-Fariman, S.A. Jazayeri-Tehrani, G. Sotoudeh, Green cardamom supplementation improves serum irisin, glucose indices, and lipid profiles in overweight or obese non-alcoholic fatty liver disease patients: a double-blind randomized placebo-controlled clinical trial. BMC Complement Altern. Med. 19, 1–11 (2019)

    Article  Google Scholar 

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Acknowledgements

We thank Mark Cleasby, PhD from Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the language of a draft of this manuscript.

Funding

Funding

This work was supported by the Natural Science Foundation of Guangdong Province (grant number 2023A1515011925) and Research Fund of Hunan Provincial Education Department (21B0361).

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Author notes

  1. These authors contributed equally: Biao Li, Ying Dong

Authors and Affiliations

  1. Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration Key Laboratory of Cosmetic Safety Evaluation, School of Public Health, Southern Medical University, Guangzhou, 510515, Guangdong, China

    Biao Li

  2. Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China

    Ying Dong & Tiancai Liu

  3. School of Sports and Arts, Hunan University of Chinese Medicine, Changsha, 410208, China

    Siyuan Hu

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  1. Biao Li
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Contributions

Conception: T.L.; Interpretation or analysis of data: S.H. Y.D. and B.L.; Preparation of the manuscript: B.L. and Y.D.; Revision for important intellectual: B.L. Y.D. and T.L.; Content: B.L. Y.D. and T.L.; Supervision: T.L. All the authors have read and approved the manuscript.

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Correspondence to Siyuan Hu or Tiancai Liu.

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Li, B., Dong, Y., Hu, S. et al. MiR-143-3p/FNDC5 axis: a novel regulator of insulin sensitivity. Endocrine 83, 368–377 (2024). https://doi.org/10.1007/s12020-023-03522-4

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