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Trans-anethole Induces Thermogenesis via Activating SERCA/SLN Axis in C2C12 Muscle Cells

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Abstract

Recently, adaptive non-shivering thermogenesis has attracted considerable attention because it can elevate energy expenditure and help treat obesity. Despite the numerous reports related to UCP1-driven thermogenesis, little is known regarding UCP1-independent thermogenesis in adipose tissues and muscle. Therefore, it is essential to identify the molecular targets for UCP1-independent thermogenesis and their mechanisms to increase the energy expenditure pharmacologically in both adipocytes and muscle. This study examined whether trans-anethole (TA), a major component of the essential oils of fennel, induces UCP1-independent SERCA/SLN-based thermogenesis and promotes the lipid metabolism in muscle cells. TA enhanced myogenesis, lipolysis, and the oxidative metabolism in C2C12 muscle cells. More importantly, TA activated the SERCA/SLN/RYR axis, thereby inducing thermogenesis in muscle cells. Molecular docking analysis revealed a good interaction between SERCA with TA with a strong bind activity. In conclusion, the current data unveiled a previously unknown mechanism of TA in myoblasts and suggests a possible therapeutic agent in muscles by enhancing energy expenditure.

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References

  1. Fuller-Jackson, J. P. and B. A. Henry (2018) Adipose and skeletal muscle thermogenesis: studies from large animals. J. Endocrinol. 237: R99–R115.

    Article  CAS  Google Scholar 

  2. Cui, X., J. Jing, R. Wu, Q. Cao, F. Li, K. Li, S. Wang, L. Yu, G. Schwartz, H. Shi, B. Xue, and H. Shi (2021) Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue. Nat. Commun. 12: 5362.

    Article  CAS  Google Scholar 

  3. Choi, M. J., S. Mukherjee, and J. W. Yun (2021) Loss of ADAMTS15 promotes browning in 3T3-L1 white adipocytes via activation of β3-adrenergic receptor. Biotechnol. Bioprocess Eng. 26: 188–200.

    Article  CAS  Google Scholar 

  4. Betz, M. J. and S. Enerbäck (2018) Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease. Nat. Rev. Endocrinol. 14: 77–87.

    Article  CAS  Google Scholar 

  5. Bal, N. C., S. K. Maurya, S. Pani, C. Sethy, A. Banerjee, S. Das, S. Patnaik, and C. N. Kundu (2017) Mild cold induced thermogenesis: are BAT and skeletal muscle synergistic partners? Biosci. Rep. 37: BSR20171087.

    Article  CAS  Google Scholar 

  6. Maurya, S. K., N. C. Bal, D. H. Sopariwala, M. Pant, L. A. Rowland, S. A. Shaikh, and M. Periasamy (2015) Sarcolipin is a key determinant of the basal metabolic rate, and its overexpression enhances energy expenditure and resistance against diet-induced obesity. J. Biol. Chem. 290: 10840–10849.

    Article  CAS  Google Scholar 

  7. Jang, M. H., S. Mukherjee, M. J. Choi, N. H. Kang, H. G. Pham, and J. W. Yun (2020) Theobromine alleviates diet-induced obesity in mice via phosphodiesterase-4 inhibition. Eur. J. Nutr. 59: 3503–3516.

    Article  CAS  Google Scholar 

  8. Periasamy, M., J. L. Herrera, and F. C. Reis (2017) Skeletal muscle thermogenesis and its role in whole body energy metabolism. Diabetes Metab. J. 41: 327–336.

    Article  Google Scholar 

  9. Ikeda, K., Q. Kang, T. Yoneshiro, J. P. Camporez, H. Maki, M. Homma, K. Shinoda, Y. Chen, X. Lu, P. Maretich, K. Tajima, K. M. Ajuwon, T. Soga, and S. Kajimura (2017) UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat. Med. 23: 1454–1465.

    Article  CAS  Google Scholar 

  10. Kus, V., T. Prazak, P. Brauner, M. Hensler, O. Kuda, P. Flachs, P. Janovska, D. Medrikova, M. Rossmeisl, Z. Jilkova, B. Stefl, E. Pastalkova, Z. Drahota, J. Houstek, and J. Kopecky (2008) Induction of muscle thermogenesis by high-fat diet in mice: association with obesity-resistance. Am. J. Physiol. Endocrinol. Metab. 295: E356–E367.

    Article  CAS  Google Scholar 

  11. Pham, H. G., J. P. Park, and J. W. Yun (2020) BMP11 negatively regulates lipid metabolism in C2C12 muscle cells. Biotechnol. Bioprocess Eng. 25: 670–680.

    Article  CAS  Google Scholar 

  12. Nowack, J., S. G. Vetter, G. Stalder, J. Painer, M. Kral, S. Smith, M. H. Le, P. Jurcevic, C. Bieber, W. Arnold, and T. Ruf (2019) Muscle nonshivering thermogenesis in a feral mammal. Sci. Rep. 9: 6378.

    Article  Google Scholar 

  13. Pant, M., N. C. Bal, and M. Periasamy (2016) Sarcolipin: a key thermogenic and metabolic regulator in skeletal muscle. Trends Endocrinol. Metab. 27: 881–892.

    Article  CAS  Google Scholar 

  14. Braun, J. L., A. C. T. Teng, M. S. Geromella, C. R. Ryan, R. K. Fenech, R. E. K. MacPherson, A. O. Gramolini, and V. A. Fajardo (2021) Neuronatin promotes SERCA uncoupling and its expression is altered in skeletal muscles of high-fat diet-fed mice. FEBS Lett. 595: 2756–2767.

    Article  CAS  Google Scholar 

  15. Periasamy, M., S. K. Maurya, S. K. Sahoo, S. Singh, F. C. Reis, and N. C. Bal (2017) Role of SERCA pump in muscle thermogenesis and metabolism. Compr. Physiol. 7: 879–890.

    Article  Google Scholar 

  16. Karri, S., S. Sharma, K. Hatware, and K. Patil (2019) Natural anti-obesity agents and their therapeutic role in management of obesity: a future trend perspective. Biomed. Pharmacother. 110: 224–238.

    Article  CAS  Google Scholar 

  17. Manigandan, S. and J. W. Yun (2020) Urolithin A induces brown-like phenotype in 3T3-L1 white adipocytes via β3-adrenergic receptor-p38 MAPK signaling pathway. Biotechnol. Bioprocess Eng. 25: 345–355.

    Article  CAS  Google Scholar 

  18. Choi, M., S. Mukherjee, and J. W. Yun (2021) Anthocyanin oligomers stimulate browning in 3T3-L1 white adipocytes via activation of the β3-adrenergic receptor and ERK signaling pathway. Phytother. Res. 35: 6281–6294.

    Article  CAS  Google Scholar 

  19. Mukherjee, S. and J. W. Yun (2022) β-Carotene stimulates browning of 3T3-L1 white adipocytes by enhancing thermogenesis via the β3-AR/p38 MAPK/SIRT signaling pathway. Phytomedicine 96: 153857.

    Article  CAS  Google Scholar 

  20. Kang, N. H., S. Mukherjee, T. Min, S. C. Kang, and J. W. Yun (2018) Trans-anethole ameliorates obesity via induction of browning in white adipocytes and activation of brown adipocytes. Biochimie 151: 1–13.

    Article  CAS  Google Scholar 

  21. Sun, W., M. H. Shahrajabian, and Q. Cheng (2019) Anise (Pimpinella anisum L.), a dominant spice and traditional medicinal herb for both food and medicinal purposes. Cogent Biol. 5: 1673688.

    Article  CAS  Google Scholar 

  22. Truhaut, R., B. Le Bourhis, M. Attia, R. Glomot, J. Newman, and J. Caldwell (1989) Chronic toxicity/carcinogenicity study of trans-anethole in rats. Food Chem. Toxicol. 27: 11–20.

    Article  CAS  Google Scholar 

  23. Tabanca, N., S. I. Khan, E. Bedir, S. Annavarapu, K. Willett, I. A. Khan, N. Kirimer, and K. H. C. Baser (2004) Estrogenic activity of isolated compounds and essential oils of Pimpinella species from Turkey, evaluated using a recombinant yeast screen. Planta Med. 70: 728–735.

    Article  CAS  Google Scholar 

  24. Nakagawa, Y. and T. Suzuki (2003) Cytotoxic and xenoestrogenic effects via biotransformation of trans-anethole on isolated rat hepatocytes and cultured MCF-7 human breast cancer cells. Biochem. Pharmacol. 66: 63–73.

    Article  CAS  Google Scholar 

  25. Aprotosoaie, A. C., I. I. Costache, and A. Miron (2016) Anethole and its role in chronic diseases. Adv. Exp. Med. Biol. 929: 247–267.

    Article  CAS  Google Scholar 

  26. Song, A., Y. Park, B. Kim, and S. G. Lee (2020) Modulation of lipid metabolism by trans-anethole in hepatocytes. Molecules 25: 4946.

    Article  CAS  Google Scholar 

  27. Freire, R. S., S. M. Morais, F. E. Catunda-Junior, and D. C. Pinheiro (2005) Synthesis and antioxidant, anti-inflammatory and gastroprotector activities of anethole and related compounds. Bioorg. Med. Chem. 13: 4353–4358.

    Article  CAS  Google Scholar 

  28. Cho, H. I., K. M. Kim, J. H. Kwak, S. K. Lee, and S. M. Lee (2013) Protective mechanism of anethole on hepatic ischemia/reperfusion injury in mice. J. Nat. Prod. 76: 1717–1723.

    Article  CAS  Google Scholar 

  29. Sheikh, B. A., L. Pari, A. Rathinam, and R. Chandramohan (2015) Trans-anethole, a terpenoid ameliorates hyperglycemia by regulating key enzymes of carbohydrate metabolism in streptozotocin induced diabetic rats. Biochimie 112: 57–65.

    Article  CAS  Google Scholar 

  30. Cavalcanti, J. M., J. H. Leal-Cardoso, L. R. L. Diniz, V. G. Portella, C. O. Costa, C. F. B. M. Linard, K. Alves, M. V. A. P. Rocha, C. C. Lima, V. M. Cecatto, and A. N. Coelho-de-Souza (2012) The essential oil of Croton zehntneri and trans-anethole improves cutaneous wound healing. J. Ethnopharmacol. 144: 240–247.

    Article  Google Scholar 

  31. Ryu, S., G. H. Seol, H. Park, and I. Y. Choi (2014) Trans-anethole protects cortical neuronal cells against oxygen-glucose deprivation/reoxygenation. Neurol. Sci. 35: 1541–1547.

    Article  Google Scholar 

  32. Mosmann, T. (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 65: 55–63.

    Article  CAS  Google Scholar 

  33. Pan, R., X. Zhu, P. Maretich, and Y. Chen (2020) Combating obesity with thermogenic fat: current challenges and advancements. Front. Endocrinol. (Lausanne) 11: 185.

    Article  Google Scholar 

  34. Kim, J., K. P. Lee, D. W. Lee, and K. Lim (2017) Piperine enhances carbohydrate/fat metabolism in skeletal muscle during acute exercise in mice. Nutr. Metab. (Lond.) 14: 43.

    Article  Google Scholar 

  35. De Blasio, A., A. D’Anneo, M. Lauricella, S. Emanuele, M. Giuliano, G. Pratelli, G. Calvaruso, and D. Carlisi (2021) The beneficial effects of essential oils in anti-obesity treatment. Int. J. Mol. Sci. 22: 11832.

    Article  CAS  Google Scholar 

  36. Rashed, A. A., M. N. Mohd Nawi, and K. Sulaiman (2017) Assessment of essential oil as a potential anti-obesity agent: a narrative review. J. Essent. Oil Res. 29: 1–10.

    Article  Google Scholar 

  37. Zhang, W., X. Li, T. Yu, L. Yuan, G. Rao, D. Li, and C. Mu (2015) Preparation, physicochemical characterization and release behavior of the inclusion complex of trans-anethole and β-cyclodextrin. Food Res. Int. 74: 55–62.

    Article  CAS  Google Scholar 

  38. Bae, J. P., M. J. Lage, D. Mo, D. R. Nelson, and B. J. Hoogwerf (2016) Obesity and glycemic control in patients with diabetes mellitus: analysis of physician electronic health records in the US from 2009–2011. J. Diabetes Complications 30: 212–220.

    Article  CAS  Google Scholar 

  39. Rhee, Y. H., J. H. Moon, J. H. Mo, T. Pham, and P. S. Chung (2018) mTOR and ROS regulation by anethole on adipogenic differentiation in human mesenchymal stem cells. BMC Cell Biol. 19: 12.

    Article  Google Scholar 

  40. Yu, C., J. Zhang, Q. Li, X. Xiang, Z. Yang, and T. Wang (2021) Effects of trans-anethole supplementation on serum lipid metabolism parameters, carcass characteristics, meat quality, fatty acid, and amino acid profiles of breast muscle in broiler chickens. Poult. Sci. 100: 101484.

    Article  CAS  Google Scholar 

  41. Lee, S. J., Y. E. Leem, G. Y. Go, Y. Choi, Y. J. Song, I. Kim, D. Y. Kim, Y. K. Kim, D. W. Seo, J. S. Kang, and G. U. Bae (2017) Epicatechin elicits MyoD-dependent myoblast differentiation and myogenic conversion of fibroblasts. PLoS One 12: e0175271.

    Article  Google Scholar 

  42. Reza, M. M., N. Subramaniyam, C. M. Sim, X. Ge, D. Sathiakumar, C. McFarlane, M. Sharma, and R. Kambadur (2017) Irisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy. Nat. Commun. 8: 1104.

    Article  Google Scholar 

  43. Abedpoor, N., F. Taghian, K. Ghaedi, I. Niktab, Z. Safaeinejad, F. Rabiee, S. Tanhaei, and M. H. Nasr-Esfahani (2018) PPARγ/Pgc-1α-Fndc5 pathway up-regulation in gastrocnemius and heart muscle of exercised, branched chain amino acid diet fed mice. Nutr. Metab. (Lond.) 15: 59.

    Article  Google Scholar 

  44. Xie, T. and P. S. Leung (2020) Roles of FGF21 and irisin in obesity-related diabetes and pancreatic diseases. J. Pancreatol. 3: 29–34.

    Article  Google Scholar 

  45. Zeng, H. L., S. L. Huang, F. C. Xie, L. M. Zeng, Y. H. Hu, and Y. Leng (2015) Yhhu981, a novel compound, stimulates fatty acid oxidation via the activation of AMPK and ameliorates lipid metabolism disorder in ob/ob mice. Acta Pharmacol. Sin. 36: 343–352.

    Article  CAS  Google Scholar 

  46. Hook, S. C., A. Chadt, K. J. Heesom, S. Kishida, H. Al-Hasani, J. M. Tavaré, and E. C. Thomas (2020) TBC1D1 interacting proteins, VPS13A and VPS13C, regulate GLUT4 homeostasis in C2C12 myotubes. Sci. Rep. 10: 17953.

    Article  Google Scholar 

  47. Samovski, D., J. Sun, T. Pietka, R. W. Gross, R. H. Eckel, X. Su, P. D. Stahl, and N. A. Abumrad (2015) Regulation of AMPK activation by CD36 links fatty acid uptake to β-oxidation. Diabetes 64: 353–359.

    Article  CAS  Google Scholar 

  48. Steinbusch, L. K., R. W. Schwenk, D. M. Ouwens, M. Diamant, J. F. Glatz, and J. J. F. P. Luiken (2011) Subcellular trafficking of the substrate transporters GLUT4 and CD36 in cardiomyocytes. Cell. Mol. Life Sci. 68: 2525–2538.

    Article  CAS  Google Scholar 

  49. Klaus, S., B. Rudolph, C. Dohrmann, and R. Wehr (2005) Expression of uncoupling protein 1 in skeletal muscle decreases muscle energy efficiency and affects thermoregulation and substrate oxidation. Physiol. Genomics 21: 193–200.

    Article  CAS  Google Scholar 

  50. Adjeitey, C. N., R. J. Mailloux, R. A. Dekemp, and M. E. Harper (2013) Mitochondrial uncoupling in skeletal muscle by UCP1 augments energy expenditure and glutathione content while mitigating ROS production. Am. J. Physiol. Endocrinol. Metab. 305: E405–E415.

    Article  CAS  Google Scholar 

  51. Grimm, M., H. Ling, A. Willeford, L. Pereira, C. B. B. Gray, J. R. Erickson, S. Sarma, J. L. Respress, X. H. T. Wehrens, D. M. Bers, and J. H. Brown (2015) CaMKIIδ mediates β-adrenergic effects on RyR2 phosphorylation and SR Ca(2+) leak and the pathophysiological response to chronic β-adrenergic stimulation. J. Mol. Cell. Cardiol. 85: 282–291.

    Article  CAS  Google Scholar 

  52. Ikeda, K. and T. Yamada (2020) UCP1 dependent and independent thermogenesis in brown and beige adipocytes. Front. Endocrinol. (Lausanne) 11: 498.

    Article  Google Scholar 

  53. Wallimann, T., M. Tokarska-Schlattner, L. Kay, and U. Schlattner (2020) Role of creatine and creatine kinase in UCP1-independent adipocyte thermogenesis. Am. J. Physiol. Endocrinol. Metab. 319: E944–E946.

    Article  CAS  Google Scholar 

  54. Kazak, L. and B. M. Spiegelman (2020) Mechanism of futile creatine cycling in thermogenesis. Am. J. Physiol. Endocrinol. Metab. 319: E947–E949.

    Article  CAS  Google Scholar 

  55. Lin, J., C. Cao, C. Tao, R. Ye, M. Dong, Q. Zheng, C. Wang, X. Jiang, G. Qin, C. Yan, K. Li, J. R. Speakman, Y. Wang, W. Jin, and J. Zhao (2017) Cold adaptation in pigs depends on UCP3 in beige adipocytes. J. Mol. Cell Biol. 9: 364–375.

    Article  CAS  Google Scholar 

  56. Hilse, K. E., A. V. Kalinovich, A. Rupprecht, A. Smorodchenko, U. Zeitz, K. Staniek, R. G. Erben, and E. E. Pohl (2016) The expression of UCP3 directly correlates to UCP1 abundance in brown adipose tissue. Biochim. Biophys. Acta 1857: 72–78.

    Article  CAS  Google Scholar 

  57. Puzzo, D., R. Raiteri, C. Castaldo, R. Capasso, E. Pagano, M. Tedesco, W. Gulisano, L. Drozd, P. Lippiello, A. Palmeri, P. Scotto, and M. C. Miniaci (2016) CL316,243, a β3-adrenergic receptor agonist, induces muscle hypertrophy and increased strength. Sci. Rep. 5: 37504.

    Article  Google Scholar 

  58. Tadini Buoninsegni, F., G. Bartolommei, M. R. Moncelli, G. Inesi, and R. Guidelli (2004) Time-resolved charge translocation by sarcoplasmic reticulum Ca-ATPase measured on a solid supported membrane. Biophys. J. 86: 3671–3686.

    Article  Google Scholar 

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Acknowledgements

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT, No. 2019R1A2C2002163).

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  1. Laboratory of Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, EPFL, CH-1015, Lausanne, Switzerland

    Sulagna Mukherjee

  2. Department of Biotechnology, Daegu University, Gyeongsan, 38453, Korea

    Minji Choi & Jong Won Yun

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  1. Sulagna Mukherjee
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Mukherjee, S., Choi, M. & Yun, J.W. Trans-anethole Induces Thermogenesis via Activating SERCA/SLN Axis in C2C12 Muscle Cells. Biotechnol Bioproc E 27, 938–948 (2022). https://doi.org/10.1007/s12257-022-0242-2

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