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Research Article | Open Access | Online First

FER1L6 ameliorates insulin resistance by regulating GLUT4 expression

Qi Tang1, Zhen-Hua Liang1, Jia-Jia Yuan1, Elsayed Hassan Hussein Shaaban4, Jin-Feng Wei1,2( ), Zhen-Hua Liu1,3( )
National R & D Center for Edible Fungus Processing Technology, Henan University, Kaifeng 475004, China
Food Laboratory of Zhongyuan, School of Life Sciences, Henan University, Kaifeng 475004, China
College of Agriculture, Henan University, Kaifeng 475004, China
Medicinal and Aromatic Plants Researches Department Horticulture Researches Institute, Agricultural Research Center, Giza 12619, Egypt
Show Author Information

Highlights

(1) Eud ameliorated insulin resistance in 3T3-L1 adipocytes, HepG2 cells through the PI3K/AKT signaling pathway.

(2) Eud can promote glucose uptake by IR-HepG2 cells by promoting glycogen synthesis and inhibiting gluconeogenesis.

(3) Inhibition of FER1L6 expression promoted GLUT4 expression to improve IR of HepG2 cells.

Graphical Abstract

In the present study, we found that Eud, a compound isolated from Xanthophyllum officinale, could alleviate insulin resistance by restoring the PI3K/AKT pathway. Meanwhile, inhibition of FER1L6 expression promoted GLUT4 expression, which improved insulin resistance. Our results provide some rationale for the therapeutic application of Eud in metabolic diseases, as well as new targets for the diagnosis and treatment of insulin resistance.

Abstract

Insulin resistance, a prominent characteristic of type 2 diabetes, has been extensively studied. In our investigation, we examined the effect of Eudesmin on insulin resistance in 3T3-L1 adipocytes and HepG2 cells. Additionally, we analyzed the alterations in mRNA expression in insulin-resistant HepG2 cells through transcriptomic techniques. Subsequently, we assessed the changes in mRNA expression in insulin-resistant HepG2 cells following Eudesmin treatment. Our analysis revealed 13 differentially expressed genes that were commonly observed. Notably, FER1L6 exhibited the most significant changes, with a marked upregulation in mRNA expression in insulin-resistant HepG2 cells. Consequently, we conducted functional experiments to validate the role of fer-1 like family member 6 (FER1L6). Specifically, through gene knockdown experiments, we observed a significant enhancement in glucose transporter type 4 (GLUT4) expression and an improvement in insulin resistance status in cell models. Therefore, FER1L6 emerges as a promising therapeutic target for insulin resistance.

Keywords

insulin resistance3T3-L1 adipocytesHepG2 cellsEudesmin

References

[1]

Zhu, X., Xu, X., Du, C., et al. An examination of the protective effects and molecular mechanisms of curcumin, a polyphenol curcuminoid in diabetic nephropathy. Biomedicine & Pharmacotherapy, 2022, 153: 113438. https://doi.org/10.1016/j.biopha.2022.113438
Crossref Google Scholar
[2]

Aalaa, M., Amini, M. R., Delavari, S., et al. Diabetic foot workshop: a strategy for improving the knowledge of diabetic foot care providers. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 2022, 16: 102543. https://doi.org/10.1016/j.dsx.2022.102543
Crossref Google Scholar
[3]

Kim, H., Lee, K. N., Shin, D. W., et al. Association of comorbid mental disorders with cardiovascular disease risk in patients with type 2 diabetes: a nationwide cohort study. General Hospital Psychiatry, 2022, 79: 33–41. https://doi.org/10.1016/j.genhosppsych.2022.10.005
Crossref Google Scholar
[4]

Chatterjee, S., Khunti, K., Davies, M. J. Type 2 diabetes. The Lancet, 2017, 389: 2239–2251. https://doi.org/10.1016/S0140-6736(17)30058-2
Crossref Google Scholar
[5]

Nortion, L., Shannon, C., Gastaldelli, A., et al. Insulin: the master regulator of glucose metabolism. Metabolism-Clinical and Experimental, 2022, 129: 155142. https://doi.org/10.1016/j.metabol.2022.155142
Crossref Google Scholar
[6]

Van, G. J., Shun-shion, A. S., Fazakerley, D. J. Insulin signalling and GLUT4 trafficking in insulin resistance. Biochemical Society Transactions, 2023, 51: 1057–1069. https://doi.org/10.1042/BST20221066
Crossref Google Scholar
[7]

Zisman, A., Peroni, O. D., Abel, E. D., et al. Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nature Medicine, 2000, 6: 924–928. https://doi.org/10.1038/78693
Crossref Google Scholar
[8]

Abel, E. D., Peroni, O., Kim, J. K., et al. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature, 2001, 409: 729–733. https://doi.org/10.1038/35055575
Crossref Google Scholar
[9]

Carvasho, E., Kotani, K., Peroni, O. D., et al. Adipose-specific overexpression of GLUT4 reverses insulin resistance and diabetes in mice lacking GLUT4 selectively in muscle. American Journal of Physiology-Endocrinology and Metabolism, 2005, 289: E551–E561. https://doi.org/10.1152/ajpendo.00116.2005
Crossref Google Scholar
[10]

Falcetta, P., Aragona, M., Bertolotto, A., et al. Insulin discovery: a pivotal point in medical history. Metabolism-Clinical and Experimental, 2022, 127: 154941. https://doi.org/10.1016/j.metabol.2021.154941
Crossref Google Scholar
[11]

Mastrototaro, L., Roden, M. Insulin resistance and insulin sensitizing agents. Metabolism-Clinical and Experimental, 2021, 125: 154892. https://doi.org/10.1016/j.metabol.2021.154892
Crossref Google Scholar
[12]

Edgerton, D. S., Kraft, G., Smith, M., et al. Insulin's direct hepatic effect explains the inhibition of glucose production caused by insulin secretion. JCI Insight, 2017, 2: e91863. https://doi.org/10.1172/jci.insight.91863
Crossref Google Scholar
[13]

Kim, J. Y., Bacha, F., Tfayli, H., et al. 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, 2019, 42: 265–272. https://doi.org/10.2337/dc18-1178
Crossref Google Scholar
[14]

Girousse, A., Virtue, S., Hart, D., et al. Surplus fat rapidly increases fat oxidation and insulin resistance in lipodystrophic mice. Molecular Metabolism, 2018, 13: 24–29. https://doi.org/10.1016/j.molmet.2018.05.006
Crossref Google Scholar
[15]

Neeland, I. J., Ross, R., Dseprés, J. P., et al. Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: a position statement. The Lancet Diabetes & Endocrinology, 2019, 7: 715–725. https://doi.org/10.1016/S2213-8587(19)30084-1
Crossref Google Scholar
[16]

Bechmann, L. P., Hannivoort, R. A., Gerken, G., et al. The interaction of hepatic lipid and glucose metabolism in liver diseases. Journal of Hepatology, 2012, 56: 952–964. https://doi.org/10.1016/j.jhep.2011.08.025
Crossref Google Scholar
[17]

Tappy, L. Metabolism of sugars: a window to the regulation of glucose and lipid homeostasis by splanchnic organs. Clinical Nutrition, 2021, 40: 1691–1698. https://doi.org/10.1016/j.clnu.2020.12.022
Crossref Google Scholar
[18]

Demarsilis, A., Reddy, N., Boutari, C., et al. Pharmacotherapy of type 2 diabetes: an update and future directions. Metabolism-Clinical and Experimental, 2022, 137: 155332. https://doi.org/10.1016/j.metabol.2022.155332
Crossref Google Scholar
[19]

Stadler, L. K., Farooqi, I. S. A new drug target for type 2 diabetes. Cell, 2017, 170: 12–14. https://doi.org/10.1016/j.cell.2017.06.024
Crossref Google Scholar
[20]

Liu, Z., Xu, L., Xu, X., et al. Effects and mechanisms of iridoid glycosides from Patrinia scabiosaefolia on improving insulin resistance in 3T3-L1 adipocytes. Food and Chemical Toxicology, 2019, 134: 110806. https://doi.org/10.1016/j.fct.2019.110806
Crossref Google Scholar
[21]

Zhu, D., Wang, Y., Du, Q., et al. Cichoric acid reverses insulin resistance and suppresses inflammatory responses in the glucosamine-induced HepG2 cells. Journal of Agricultural and Food Chemistry, 2015, 63: 10903–10913. https://doi.org/10.1021/acs.jafc.5b04533
Crossref Google Scholar
[22]

Cui, L., Wang, J., Wang, M., et al. Chemical composition and glucose uptake effect on 3T3-L1 adipocytes of Ligustrum lucidum Ait. flowers. Food Science and Human Wellness, 2020, 9: 124–129. https://doi.org/10.1016/j.fshw.2020.02.002
Crossref Google Scholar
[23]

Tang, Q., Chen, S., Rizvi, S. A. H., et al. Two alkaloids from Delphinium brunonianum Royle, their anti-inflammatory and anti-oxidative stress activity via NF-κB signaling pathway. Frontiers in Nutrition, 2021, 8: 826957. https://doi.org/10.3389/fnut.2021.826957
Crossref Google Scholar
[24]

Zhang, Y., Lv, P., Ma, J., et al. Antrodia cinnamomea exerts an anti-hepatoma effect by targeting PI3K/AKT-mediated cell cycle progression in vitro and in vivo. Acta Pharmaceutica Sinica B, 2022, 12: 890–906. https://doi.org/10.1016/j.apsb.2021.07.010
Crossref Google Scholar
[25]

Huang, X., Liu, G., Guo, J., et al. The PI3K/AKT pathway in obesity and type 2 diabetes. International Journal of Biological Sciences, 2018, 14: 1483–1496. https://doi.org/10.7150/ijbs.27173
Crossref Google Scholar
[26]

Posey, A. D., Pytel, P., Gardikiotes, K., et al. Endocytic recycling proteins EHD1 and EHD2 interact with fer-1-like-5 (Fer1L5) and mediate myoblast fusion. Journal of Biological Chemistry, 2011, 286: 7379–7388. https://doi.org/10.1074/jbc.M110.157222
Crossref Google Scholar
[27]

Park, S. Y., Ha, B. G., Choi, G. H., et al. EHD2 interacts with the insulin-responsive glucose transporter (GLUT4) in rat adipocytes and may participate in insulin-induced GLUT4 recruitment. Biochemistry, 2004, 43: 7552–7562. https://doi.org/10.1021/bi049970f
Crossref Google Scholar
[28]
Fazakerley, D. J., Krycer, J. R., Kearney, A. L., et al. Muscle and adipose tissue insulin resistance: malady without mechanism? Journal of Lipid Research, 2019 , 60: 1720–1732. https://doi.org/10.1194/jlr.R087510
Crossref
[29]
Kim, J. Y., Lim, H. J., Lee, D. Y., et al. In vitro anti-inflammatory activity of lignans isolated from Magnolia fargesii. Bioorganic & Medicinal Chemistry Letters, 2009 , 19: 937–940. https://doi.org/10.1016/j.bmcl.2008.11.103
Crossref
[30]

Yu, M., Li, Y., Li, M., et al. Eudesmin exerts antitumor effects by down-regulating EZH2 expression in nasopharyngeal carcinoma cells. Chemico-Biological Interactions, 2019, 307: 51–57. https://doi.org/10.1016/j.cbi.2019.04.028
Crossref Google Scholar
[31]

Liu, H., Song, Z., Liao, D. G., et al. Anticonvulsant and sedative effects of Eudesmin isolated from Acorus tatarinowii on mice and rats. Phytotherapy Research, 2015, 29: 996–1003. https://doi.org/10.1002/ptr.5337
Crossref Google Scholar
[32]

Nam, K. H., Yi, S. A., Lee, J., et al. Eudesmin impairs adipogenic differentiation via inhibition of S6K1 signaling pathway. Biochemical and Biophysical Research Communications, 2018, 505: 1148–1153. https://doi.org/10.1016/j.bbrc.2018.09.188
Crossref Google Scholar
[33]

Nurcahyanti, A. D. R., Jap, A., Lady, J., et al. Function of selected natural antidiabetic compounds with potential against cancer via modulation of the PI3K/AKT/mTOR cascade. Biomedicine & Pharmacotherapy, 2021, 144: 112138. https://doi.org/10.1016/j.biopha.2021.112138
Crossref Google Scholar
[34]

Yan, J., Wang, C., Jin, Y., et al. Catalpol ameliorates hepatic insulin resistance in type 2 diabetes through acting on AMPK/NOX4/PI3K/AKT pathway. Pharmacological Research, 2018, 130: 466–480. https://doi.org/10.1016/j.phrs.2017.12.026
Crossref Google Scholar
[35]

Gao, C., Fei, X., Wang, M., et al. Cardamomin protects from diabetes-induced kidney damage through modulating PI3K/AKT and JAK/STAT signaling pathways in rats. International Immunopharmacology, 2022, 107: 108610. https://doi.org/10.1016/j.intimp.2022.108610
Crossref Google Scholar
[36]

Klein, S., Gastaldelli, A., Yki-Järvinen, H., et al. Why does obesity cause diabetes. Cell Metabolism, 2022, 34: 11–20. https://doi.org/10.1016/j.cmet.2021.12.012
Crossref Google Scholar
[37]

Hutchison, A. L., Tavaglione, F., Romeo, S., et al. Endocrine aspects of metabolic dysfunction associated steatotic liver disease (MASLD): beyond insulin resistance. Journal of Hepatology, 2023, 79: 1524–1541. https://doi.org/10.1016/j.jhep.2023.08.030
Crossref Google Scholar
[38]

Han, H. S., Kang, G., Kim, J. S., et al. Regulation of glucose metabolism from a liver-centric perspective. Experimental and Molecular Medicine, 2016, 48: e218. https://doi.org/10.1038/emm.2015.122
Crossref Google Scholar
[39]

Shen, X., Luo, K., Yuan, J., et al. Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: involvement of reduced S100A11 expression. Acta Pharmaceutica Sinica B, 2023, 13: 3352–3364. https://doi.org/10.1016/j.apsb.2023.05.020
Crossref Google Scholar
[40]

Kumar, S., Chhimwal, J., Kumar, S., et al. Phloretin and phlorizin mitigates inflammatory stress and alleviate adipose and hepatic insulin resistance by abrogating PPARγ S273-Cdk5 interaction in type 2 diabetic mice. Life Sciences, 2023, 322: 121668. https://doi.org/10.1016/j.lfs.2023.121668
Crossref Google Scholar
[41]

Long, F., Bhatti, M. R., Kellenberger, A., et al. A low-carbohydrate diet induces hepatic insulin resistance and metabolic associated fatty liver disease in mice. Molecular Metabolism, 2023, 69: 101675. https://doi.org/10.1016/j.molmet.2023.101675
Crossref Google Scholar
[42]

Alemayehu, B., Liu, J., Rajpathak, S., et al. Healthcare resource use and associated costs of hypoglycemia in patients with type 2 diabetes prescribed sulfonylureas. Journal of Diabetes and Its Complications, 2017, 31: 1620–1623. https://doi.org/10.1016/j.jdiacomp.2017.07.012
Crossref Google Scholar
[43]

Grytsai, O., Myrgorodska, I., Rocchi, S., et al. Biguanides drugs: past success stories and promising future for drug discovery. European Journal of Medicinal Chemistry, 2021, 224: 113726. https://doi.org/10.1016/j.ejmech.2021.113726
Crossref Google Scholar
[44]

Wu, D., Eead, V., Undi, R. B., et al. A novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice. Molecular Metabolism, 2021, 54: 101363. https://doi.org/10.1016/j.molmet.2021.101363
Crossref Google Scholar
[45]

Vinoth, K. T., Lakshmanasenthil, S., Geetharamani, D., et al. Fucoidan–a α- D-glucosidase inhibitor from Sargassum wightii with relevance to type 2 diabetes mellitus therapy. International Journal of Biological Macromolecules, 2015, 72: 1044–1047. https://doi.org/10.1016/j.ijbiomac.2014.10.013
Crossref Google Scholar
[46]

Manaithiya, A., Alam, O., Sharma, V., et al. GPR119 agonists: novel therapeutic agents for type 2 diabetes mellitus. Bioorganic Chemistry, 2021, 113: 104998. https://doi.org/10.1016/j.bioorg.2021.104998
Crossref Google Scholar
[47]

Joshi, D., Prashant, G. J., Gohsh, S., et al. TRC150094, a novel mitochondrial modulator, reduces cardio-metabolic risk as an add-on treatment: a phase-2, 24-week, multi-center, randomized, double-blind, clinical trial. Diabetes Metabolic Syndrome and Obesity, 2022, 15: 615–631. https://doi.org/10.2147/DMSO.S330515
Crossref Google Scholar
[48]

Demonbreun, A. R., Posey, A. D., Heretis, K., et al. Myoferlin is required for insulin-like growth factor response and muscle growth. FASEB Journal, 2010, 24: 1284–1295. https://doi.org/10.1096/fj.09-136309
Crossref Google Scholar
Food & Medicine Homology
DOI: 10.26599/FMH.2025.9420070
Cite this article:
Tang Q, Liang Z-H, Yuan J-J, et al. FER1L6 ameliorates insulin resistance by regulating GLUT4 expression. Food & Medicine Homology, 2025, https://doi.org/10.26599/FMH.2025.9420070

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Received: 15 July 2024
Revised: 20 August 2024
Accepted: 20 August 2024
Published: 25 December 2024
© National R & D Center for Edible Fungus Processing Technology 2024. Published by Tsinghua University Press.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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