Skip to main content

Advertisement

SpringerLink
Log in

1,3,5,8-Tetrahydroxyxanthone suppressed adipogenesis via activating Hedgehog signaling in 3T3-L1 adipocytes

  • Research Article
  • Published:
Food Science and Biotechnology Aims and scope Submit manuscript

A Correction to this article was published on 29 April 2023

This article has been updated

Abstract

In this study, we investigated the effect of 1,3,5,8-tetrahydroxyxanthone (THX) on the adipogenesis of 3T3-L1 adipocytes. THX, a xanthone isolated from Gentianella acuta, inhibited lipid accumulation in 3T3-L1 adipocytes and reduced the protein levels of the key adipogenic transcriptional factors, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), in a dose-dependent manner. In addition, THX enhanced the transcriptional activity of Gli1 known as the key indicator of Hedgehog (Hh) signaling activity and increased the expression of Gli1 and its upstream regulator Smo. The Smo activator SAG exerted the similar effect with THX on regulating Gli1, Smo, PPARγ and C/EBPα expression, which led to the suppression of fat formation in 3T3-L1 adipocytes. Furthermore, we found that the inhibitory effect of THX on adipogenesis was derived from regulation of the early stage of adipogenesis. These results suggest that THX suppresses the differentiation of adipocyte through Hh signaling and may be considered as a potent agent for the prevention of obesity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Change history

References

  • Ali AT, Hochfeld WE, Myburgh R, Pepper MS. Adipocyte and adipogenesis. European Journal of Cell Biology. 92: 229-236 (2013)

    Article  CAS  PubMed  Google Scholar 

  • Baek SC, Nam KH, Yi SA, Jo MS, Lee KH, Lee YH, Lee J, Kim KH. Anti-adipogenic effect of beta-carboline alkaloids from garlic (Allium sativum). Foods. 8:673 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Briscoe J, Therond PP. The mechanisms of Hedgehog signalling and its roles in development and disease. Nature Reviews Molecular Cell Biology. 14: 416-429 (2013)

    Article  PubMed  Google Scholar 

  • Chen J, Bao C, Kim JT, Cho JS, Qiu S, Lee HJ. Sulforaphene inhibition of adipogenesis via hedgehog signaling in 3T3-L1 adipocytes. Journal of Agricultural and Food Chemistry. 66: 11926-11934 (2018)

    Article  CAS  PubMed  Google Scholar 

  • Choi YH, Bae JK, Chae HS, Kim YM, Sreymom Y, Han L,Jang HY, Chin YW. alpha-mangostin regulates hepatic steatosis and obesity through SirT1-AMPK and PPARgamma pathways in high-fat diet-induced obese mice. Journal of Agricultural and Food Chemistry. 63: 8399-406 (2015)

    Article  CAS  PubMed  Google Scholar 

  • Davenport JR, Watts AJ, Roper VC, Croyle MJ, van Groen T, Wyss JM, Nagy TR, Kesterson RA, Yoder BK. Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Current Biology. 17:1586-1594 (2007)

    Article  CAS  PubMed  Google Scholar 

  • de Sa PM, Richard AJ, Hang H, Stephens JM. Transcriptional regulation of adipogenesis. Genes & Development. 7: 635-674 (2017)

    Google Scholar 

  • Ding Z, Liu Y, Ruan J, Yang S, Yu H, Chen M, Zhang Y ,Wang T. Bioactive constituents from the whole plants of Gentianella acuta (Michx.) Hulten. Molecules. 22:1309 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  • Field AE, Coakley EH, Must A, Spadano JL, Laird N, Dietz WH, Rimm E ,Colditz GA. Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Archives of Internal Medicine. 161: 1581-1586 (2001)

    Article  CAS  PubMed  Google Scholar 

  • Geum NG, Son HJ, Yeo JH, Yu JH, Choi MY, Lee JW, Baek JK, Jeong JB. Anti-obesity activity of Heracleum moellendorffii root extracts in 3T3-L1 adipocytes. Food Science & Nutrition. 9: 5939-5945 (2021)

    Article  CAS  Google Scholar 

  • Haider N, Larose L. Harnessing adipogenesis to prevent obesity. Adipocyte. 8: 98-104 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  • Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS. Obesity and the risk of heart failure. New England Journal of Medicine. 347: 305-313 (2002)

    Article  PubMed  Google Scholar 

  • Kim WK, Meliton V, Amantea CM, Hahn, TJ, Parhami F. 20(S)-hydroxycholesterol inhibits PPARgamma expression and adipogenic differentiation of bone marrow stromal cells through a hedgehog-dependent mechanism. Journal of Bone and Mineral Research. 22: 1711-1719 (2007)

    Article  CAS  PubMed  Google Scholar 

  • Lefterova MI, Lazar MA. New developments in adipogenesis. Trends in Endocrinology & Metabolism. 20: 107-114 (2009)

    Article  CAS  Google Scholar 

  • Linhart HG, Ishimura-Oka K, DeMayo F, Kibe T, Repka D, Poindexter B, Bick RJ, Darlington GJ. C/EBPalpha is required for differentiation of white, but not brown, adipose tissue. Proceedings of the National Academy of Sciences. 98: 12532-12537 (2001)

    Article  CAS  Google Scholar 

  • Loos RJF, Yeo GSH. The genetics of obesity: from discovery to biology. Nature Reviews Genetics. 23: 120-133 (2022)

    Article  CAS  PubMed  Google Scholar 

  • Madsen MS, Siersbaek R, Boergesen M, Nielsen R, Mandrup S. Peroxisome proliferator-activated receptor gamma and C/EBPalpha synergistically activate key metabolic adipocyte genes by assisted loading. Molecular and Cellular Biology. 34: 939-954 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  • Ni Y, Liu M, Yu H, Chen Y, Liu Y, Chen S, Ruan J, Da A, Zhang Y ,Wang T. Desmethylbellidifolin from Gentianella acuta ameliorate TNBS-induced ulcerative colitis through antispasmodic effect and anti-inflammation. Frontiers in Pharmacology. 10: 1104 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pospisilik JA, Schramek D, Schnidar H, Cronin SJ, Nehme NT, Zhang X, Knauf C, Cani PD, Aumayr K, Todoric J, Bayer M, Haschemi A, Puviindran V, Tar K, Orthofer M, Neely GG, Dietzl G, Manoukian A, Funovics M, Prager G, Wagner O, Ferrandon D, Aberger F, Hui CC, Esterbauer H, Penninger JM. Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate. Cell. 140: 148-160 (2010)

    Article  CAS  PubMed  Google Scholar 

  • Qiu S, Cho JS, Kim JT, Moon JH, Zhou Y, Lee SB, Park HJ, Lee HJ. Caudatin suppresses adipogenesis in 3T3-L1 adipocytes and reduces body weight gain in high-fat diet-fed mice through activation of hedgehog signaling. Phytomedicine. 92: 153715 (2021)

    Article  CAS  PubMed  Google Scholar 

  • Reyes C, Leyland KM, Peat G, Cooper C, Arden NK, PrietoAlhambra D. Association between overweight and obesity and risk of clinically diagnosed knee, hip, and hand osteoarthritis: a population-based cohort study. Arthritis & Rheumatology. 68: 1869-1875 (2016)

    Article  Google Scholar 

  • Ritter A, Kreis NN, Roth S. Friemel A, Jennewein L, Eichbaum C, Solbach C, Louwen F, Yuan J. Restoration of primary cilia in obese adipose-derived mesenchymal stem cells by inhibiting Aurora A or extracellular signal-regulated kinase. Stem cell research & therapy. 10: 255 (2019)

    Article  Google Scholar 

  • Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 444: 847-853 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Molecular Cell. 4: 611-617 (1999)

    Article  CAS  PubMed  Google Scholar 

  • Rosen ED, Hsu CH, Wang X, Sakai S, Freeman MW, Gonzalez FJ, Spiegelman BM. C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway. Genes & Development. 16: 22-26 (2002)

    Article  CAS  Google Scholar 

  • Seo YJ, Kim KJ, Choi J, Koh EJ, Lee BY. Spirulina maxima extract reduces obesity through suppression of adipogenesis and activation of browning in 3T3-L1 cells and high-fat diet-induced obese mice. Nutrients. 10: 712 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  • Shi Y, Long F. Hedgehog signaling via Gli2 prevents obesity induced by high-fat diet in adult mice. Elife. 6:e31649 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  • Skoda AM, Simovic D, Karin V, Kardum V, Vranic S, Serman, L. The role of the Hedgehog signaling pathway in cancer: A comprehensive review. Bosnian Journal of Basic Medical Sciences. 18: 8-20 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang QQ, Zhang JW, Daniel Lane M. Sequential gene promoter interactions by C/EBPbeta, C/EBPalpha, and PPARgamma during adipogenesis. Biochemical and Biophysical Research Communications. 318: 213-218 (2004)

    Article  CAS  PubMed  Google Scholar 

  • Tang Y, Liu J, Wang H, Li Y, Liu Z ,Chen H. 1,3,5,8-Tetrahydroxy-9H-xanthen-9-one exerts its antiageing effect through the regulation of stress-response genes and the MAPK signaling pathway. Arch Pharm Chemistry in Life Science. 352: 1900100 (2019)

    Article  Google Scholar 

  • Vaisse C, Reiter JF, Berbari NF. Cilia and Obesity. Cold Spring Harbor Perspectives in Biology. 9: a028217 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang Z, Wu G, Liu H, Xing N, Sun Y, Zhai Y, Yang B, Kong AT, Kuang H, Wang Q. Cardioprotective effect of the xanthones from Gentianella acuta against myocardial ischemia/reperfusion injury in isolated rat heart. Biomedicine & Pharmacotherapy. 93: 626-635 (2017)

    Article  CAS  Google Scholar 

  • Xiao HB, Sun ZL, Zhou N. 1,3,5,8-tetrahydroxyxanthone regulates ANGPTL3-LPL pathway to lessen the ketosis in mice. European Journal of Pharmaceutical Sciences. 46: 26-31 (2012)

    Article  CAS  PubMed  Google Scholar 

  • Yao L, Tichy ED, Zhong L, Mohanty S, Wang L, Ai E, Yang S, Mourkioti F, Qin L. Gli1 defines a subset of fibro-adipogenic progenitors that promote skeletal muscle regeneration with less fat accumulation. Journal of Bone and Mineral Research. 36: 1159-1173 (2021)

    Article  CAS  PubMed  Google Scholar 

  • Zheng HH, Luo CT, Chen H, Lin JN, Ye CL, Mao SS, Li YL. Xanthones from Swertia mussotii as multitarget-directed antidiabetic agents. ChemMedChem. 9: 1374-1377 (2014)

    Article  CAS  PubMed  Google Scholar 

  • Zhi D, Evan D, Regina B, Stefanie H, Guillaume A, Amy E, Catherine M, Gretchen J ,Bruce M. Cross-regulation of C/EBPα and PPARγ controls the transcriptional pathway of adipogenesis and insulin sensitivity. Molecular Cell. 3: 151-158 (1999)

    Article  Google Scholar 

  • Zuo Y, Qiang L, Farmer SR. Activation of CCAAT/enhancer-binding protein (C/EBP) alpha expression by C/EBP beta during adipogenesis requires a peroxisome proliferator-activated receptor-gamma-associated repression of HDAC1 at the C/ebp alpha gene promoter. Journal of Biological Chemistry. 281: 7960-7967 (2006)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was funded by the National Research Foundation of Korea (NRF-2021R1F1A1063279) and the Bio-Synergy Research Project (NRF-2013M3A9C4078156) of the Ministry of Science, ICT, and Future Planning. This study was also supported by the Chung-Ang University Graduate Research Scholarship (Academic Scholarship for the College of Biotechnology and Natural Resources) in 2022.

Author information

Authors and Affiliations

  1. Department of Food Science and Biotechnology, Chung-Ang University, Anseong, 17546, South Korea

    Yimeng Zhou, Jin Tae Kim, Shuai Qiu, Seung Beom Lee, Ho Jin Park, Moon Jeong Soon & Hong Jin Lee

Authors
  1. Yimeng Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin Tae Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuai Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seung Beom Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ho Jin Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Moon Jeong Soon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hong Jin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hong Jin Lee.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, Y., Kim, J.T., Qiu, S. et al. 1,3,5,8-Tetrahydroxyxanthone suppressed adipogenesis via activating Hedgehog signaling in 3T3-L1 adipocytes. Food Sci Biotechnol 31, 1473–1480 (2022). https://doi.org/10.1007/s10068-022-01130-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10068-022-01130-y

Keywords

Search

Navigation