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4β-Hydroxywithanolide E and withanolide E from Physalis peruviana L. inhibit adipocyte differentiation of 3T3-L1 cells through modulation of mitotic clonal expansion

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Obesity is a risk factor for many diseases, including type 2 diabetes and cardiovascular disease, and is related to the rising morbidity and mortality. Discovery of agents targeting adipogenesis, especially from natural sources, is important for the treatment of obesity. Here, we aimed to identify anti-adipogenic substances in methanol extracts of Physalis peruviana and to investigate their effect, along with underlying mechanisms. Activity-guided fractionation of the extract revealed 4β-hydroxywithanolide E (HWE) and withanolide E (WE) as the adipogenesis inhibitors. Both compounds suppressed mRNA expression of central adipogenic transcription factors, peroxisome proliferator-activated receptor γ, and CCAAT/enhancer-binding protein α in the early stage of adipocyte differentiation. The inhibitory action of these two withanolides on adipogenesis was largely limited to this stage. The proliferation of preadipocytes was markedly suppressed by treatment with HWE and WE for 24 and 48 h in the differentiation medium, and cell-cycle arrest in the G0/G1 phase was observed. Therefore, our results suggested that withanolides from P. peruviana to be novel anti-adipogenic compounds that modulate mitotic clonal expansion.

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  1. Kopelman PG (2000) Obesity as a medicinal problem. Nature 404:635–643

    Article  CAS  Google Scholar 

  2. Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, Blomqvist L, Hoffstedt J, Näslund E, Britton T, Concha H, Hassan M, Rydén M, Frisén J, Arner P (2008) Dynamics of fat cell turnover in humans. Nature 453:783–787

    Article  CAS  Google Scholar 

  3. Newman DJ, Cragg GM (2020) Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 83:770–803

    Article  CAS  Google Scholar 

  4. Kim CY, Le TT, Chen C, Cheng JX, Kim KH (2011) Curcumin inhibits adipocyte differentiation through modulation of mitotic clonal expansion. J Nutr Biochem 22:910–920

    Article  CAS  Google Scholar 

  5. Misawa N, Hosoya T, Yoshida S, Sugimoto O, Yamada-Kato T, Kumazawa S (2018) 5-Hydroxyferulic acid methyl ester isolated from wasabi leaves inhibits 3T3-L1 adipocyte differentiation. Phyther Res 32:1304–1310

    Article  CAS  Google Scholar 

  6. Drira R, Chen S, Sakamoto K (2011) Oleuropein and hydroxytyrosol inhibit adipocyte differentiation in 3T3-L1 cells. Life Sci 89:708–716

    Article  CAS  Google Scholar 

  7. Oikawa N, Nobushi Y, Wada T, Sonoda K, Okazaki Y, Tsutsumi S, Park YK, Kurokawa M, Shimba S, Yasukawa K (2016) Inhibitory effects of compounds isolated from the dried branches and leaves of murta (Myrceugenia euosma) on lipid accumulation in 3T3-L1 cells. J Nat Med 70:502–509

    Article  CAS  Google Scholar 

  8. Puente LA, Pinto-Muñoz CA, Castro ES, Cortés M (2011) Physalis peruviana Linnaeus, the multiple properties of a highly functional fruit: a review. Food Res Int 44:1733–1740

    Article  CAS  Google Scholar 

  9. Ramadan MF (2011) Bioactive phytochemicals, nutritional value, and functional properties of cape gooseberry (Physalis peruviana): an overview. Food Res Int 44:1830–1836

    Article  CAS  Google Scholar 

  10. Sakurai K, Ishii H, Kobayashi S, Iwao T (1976) Isolation of 4β-hydroxywithanolide E, a new withanolide from Physalis peruviana L. Chem Pharm Bull 24:1403–1405

    Article  CAS  Google Scholar 

  11. Kirson I, Abraham A, Sethi PD, Subramanian S, Glotter E (1975) 4β-Hydroxywithanolide E, a new natural steroid with a 17α-oriented side-chain. Phytochemistry 15:340–342

    Article  Google Scholar 

  12. Ascher KRS, Nemny NE, Eliyahu M, Kirson I, Abraham A, Glotter E (1980) Insect antifeedant properties of withanolides and related steroids from Solanaceae. Experientia 36:998–999

    Article  CAS  Google Scholar 

  13. Ascher KRS, Eliyahu M, Glotter E, Goldman A, Kirson I, Abraham A, Jacobson M, Schmutterer H (1987) The antifeedant effect of some new withanolides on three insect species, spodoptera littoralis, epilachna varivestis and tribolium castaneum. Phytoparasitica 15:15–29

    Article  CAS  Google Scholar 

  14. Baumann TW, Meier CM (1993) Chemical defence by withanolides during fruit development in Physalis peruviana. Phytochemistry 33:317–321

    Article  CAS  Google Scholar 

  15. Shingu K, Miyagawa M, Yahara S, Nohara T (1993) Physapruins A and B, two new withanolides from Physalis pruinosa bailey. Chem Pharm Bull 41:1873–1875

    Article  CAS  Google Scholar 

  16. Park EJ, Sang-Ngern M, Chang LC, Pezzuto JM (2019) Physalactone and 4β-hydroxywithanolide E isolated from Physalis peruviana inhibit LPS-induced expression of COX-2 and iNOS accompanied by abatement of Akt and STAT1. J Nat Prod 82:492–499

    Article  CAS  Google Scholar 

  17. Sang-Ngern M, Youn UJ, Park EJ, Kondratyuk TP, Simmons CJ, Wall MM, Ruf M, Lorch SE, Leong E, Pezzuto JM, Chang LC (2016) Withanolides derived from Physalis peruviana (Poha) with potential anti-inflammatory activity. Bioorg Med Chem Lett 26:2755–2759

    Article  CAS  Google Scholar 

  18. Takimoto T, Kanbayashi Y, Toyoda T, Adachi Y, Furuta C, Suzuki K, Miwa T, Bannai M (2014) 4β-Hydroxywithanolide E isolated from Physalis pruinosa calyx decreases inflammatory responses by inhibiting the NF-κB signaling in diabetic mouse adipose tissue. Int J Obes 38:1432–1439

    Article  CAS  Google Scholar 

  19. Tang QQ, Otto TC, Daniel Lane M (2003) Mitotic clonal expansion: a synchronous process required for adipogenesis. Proc Natl Acad Sci USA 100:44–49

    Article  CAS  Google Scholar 

  20. Farmer SR (2006) Transcriptional control of adipocyte formation. Cell Metab 4:263–273

    Article  CAS  Google Scholar 

  21. Rosen ED, Spiegelman BM (2000) Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol 16:145–171

    Article  CAS  Google Scholar 

  22. Trepel J, Mollapour M, Giaccone G, Neckers L (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10:537–549

    Article  CAS  Google Scholar 

  23. Park EJ, Sang-Ngern M, Chang LC, Pezzuto JM (2016) Induction of cell cycle arrest and apoptosis with downregulation of Hsp90 client proteins and histone modification by 4β-hydroxywithanolide E isolated from Physalis peruviana. Mol Nutr Food Res 60:1482–1500

    Article  CAS  Google Scholar 

  24. Nguyen MT, Csermely P, Sodblacti C (2013) Hsp90 chaperones PPARγ and regulates differentiation and survival of 3T3-L1 adipocytes. Cell Death Differ 20:1654–1663

    Article  CAS  Google Scholar 

  25. Desarzens S, Liao WH, Mammi C, Caprio M, Faresse N (2014) Hsp90 blockers inhibit adipocyte differentiation and fat mass accumulation. PLoS ONE 9:1–11736

    Article  Google Scholar 

  26. He Y, Li Y, Zhang S, Perry B, Zhao T, Wang Y, Sun C (2013) Radicicol, a heat shock protein 90 inhibitor, inhibits differentiation and adipogenesis in 3T3-L1 preadipocytes. Biochem Biophys Res Commun 436:169–174

    Article  CAS  Google Scholar 

  27. Gu M, Yu Y, Gunaherath GMKB, Gunatilaka AAL, Li D, Sun D (2014) Structure-activity relationship (SAR) of withanolides to inhibit Hsp90 for its activity in pancreatic cancer cells. Invest New Drugs 32:68–74

    Article  CAS  Google Scholar 

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The authors thank Mr. Hideo Kaseki at Fujimi Sky Farm for providing plant samples. The authors also would like to thank Dr. Munetomo Nakamura and Mr. Masatoshi Watai at Japan Food Research Laboratories for their useful comments and suggestions about the study.

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Correspondence to Momochika Kumagai.

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Kumagai, M., Yoshida, I., Mishima, T. et al. 4β-Hydroxywithanolide E and withanolide E from Physalis peruviana L. inhibit adipocyte differentiation of 3T3-L1 cells through modulation of mitotic clonal expansion. J Nat Med 75, 232–239 (2021).

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