Original Article | Published:

Animal Models

Embelin attenuates adipogenesis and lipogenesis through activating canonical Wnt signaling and inhibits high-fat diet-induced obesity

International Journal of Obesity volume 41, pages 729738 (2017) | Download Citation

Abstract

Background:

Recent studies suggest that Embelin, a natural plant extract might have the potential to prevent body weight gain in rats. However, the mechanisms involved remain to be elucidated.

Methods:

Effects of Embelin on adipocyte differentiation and lipogenesis were studied in murine ST2 stromal cells and C3H10T1/2 mesenchymal cells. The mechanisms through which Embelin regulates adipogenic differentiation and lipogenesis were explored. The in vivo anti-obesity effects of Embelin in high-fat diet (HFD)-induced obesity mice and possible transcriptional impact were investigated.

Results:

Embelin treatment suppressed ST2 and C3H10T1/2 cells to proliferate, and differentiate into mature adipocytes, along with the inhibition of adipogenic factors peroxisome proliferator-activated receptor γ, CCAAT/enhancer binding protein-α, adipocyte protein 2 and adipsin. Embelin treatment also decreased the expression levels of lipogenic factors sterol regulatory element-binding protein 1, fatty acid synthase, acetyl-CoA carboxylase 1 and stearoyl-Coenzyme A desaturase 1. Embelin promoted the translocation of β-catenin from the cytoplasm into the nucleus in C3H10T1/2. The nuclear protein levels of β-catenin and TCF-4 were increased following Embelin treatment. Furthermore, Dickkopf-1 (Dkk1) expression was downregulated by Embelin, and overexpression of Dkk1 in C3H10T1/2 reversed the inhibition of adipogenesis and lipogenesis by Embelin. In vivo studies showed that Embelin treatment reduced the gain of body weight and fat, decreased the serum level of triglycerides, free fatty acid and total cholesterol, and improved glucose tolerance and insulin resistance in HFD-fed mice. Moreover, Embelin blocked induction of adipogenic and lipogenic factors and Dkk1 in adipose tissue in HFD-fed mice.

Conclusions:

The present work provides evidences that Embelin is effective in inhibiting adipogenesis and lipogenesis in vitro and the mechanisms may involve canonical Wnt signaling. Embelin has the potential to prevent body weight gain and fat accumulation, and to improve obesity-related glucose tolerance impairment and insulin resistance in the HFD-fed mice.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , . Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994; 79: 1147–1156.

  2. 2.

    , , . Transcriptional networks and chromatin remodeling controlling adipogenesis. Trends Endocrinol Metab 2012; 23: 56–64.

  3. 3.

    , . CCAAT/enhancer binding protein alpha is sufficient to initiate the 3T3-L1 adipocyte differentiation program. Proc Natl Acad Sci USA 1994; 91: 8757–8761.

  4. 4.

    , , , , . Misexpression of CCAAT/enhancer binding protein beta causes osteopenia. J Endocrinol 2009; 201: 263–274.

  5. 5.

    , , , , , et al. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest 2004; 113: 846–855.

  6. 6.

    , , , , , et al. Selective disruption of PPARgamma 2 impairs the development of adipose tissue and insulin sensitivity. Proc Natl Acad Sci USA 2004; 101: 10703–10708.

  7. 7.

    , . Instruction of mesenchymal cell fate by the transcription factor C/EBPbeta. Gene 2012; 497: 10–17.

  8. 8.

    , , . Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells. Genes Dev 1994; 8: 1654–1663.

  9. 9.

    , , , , , et al. C/EBPalpha is required for differentiation of white, but not brown, adipose tissue. Proc Natl Acad Sci USA 2001; 98: 12532–12537.

  10. 10.

    , , , , , et al. Impaired energy homeostasis in C/EBP alpha knockout mice. Science 1995; 269: 1108–1112.

  11. 11.

    , , , . Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J 1997; 16: 7432–7443.

  12. 12.

    , , . An allostatic control of membrane lipid composition by SREBP1. FEBS Lett 2010; 584: 2689–2698.

  13. 13.

    , , , , , et al. miR-140-5p regulates adipocyte differentiation by targeting transforming growth factor-beta signaling. Sci Rep 2015; 5: 18118.

  14. 14.

    , , , , , et al. miR-223 regulates adipogenic and osteogenic differentiation of mesenchymal stem cells through a C/EBPs/miR-223/FGFR2 regulatory feedback loop. Stem Cells 2015; 33: 1589–1600.

  15. 15.

    , , , , , et al. miR-20a regulates adipocyte differentiation by targeting lysine-specific demethylase 6b and transforming growth factor-beta signaling. Int J Obes 2015; 39: 1282–1291.

  16. 16.

    , , , , , . Protective effect of embelin from Embelia ribes Burm. against transient global ischemia-induced brain damage in rats. Neurotox Res 2011; 20: 379–386.

  17. 17.

    , , , , , et al. Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J Med Chem 2004; 47: 2430–2440.

  18. 18.

    , , , , . Synthesis and evaluation of analgesic and anti-inflammatory activities of most active free radical scavenging derivatives of embelin-A structure-activity relationship. Chem Pharm Bull 2011; 59: 913–919.

  19. 19.

    , , , , , et al. Potent inhibition of human 5-lipoxygenase and microsomal prostaglandin E(2) synthase-1 by the anti-carcinogenic and anti-inflammatory agent embelin. Biochem Pharmacol 2013; 86: 476–486.

  20. 20.

    , , . Free radical scavenging reactions and antioxidant activity of embelin: biochemical and pulse radiolytic studies. Chem Biol Interact 2007; 167: 125–134.

  21. 21.

    , , , . Effects of embelin on lipid peroxidation and free radical scavenging activity against liver damage in rats. Basic Clin Pharmacol Toxicol 2009; 105: 243–248.

  22. 22.

    , . Embelin accelerates cutaneous wound healing in diabetic rats. J Asian Nat Prod Res 2013; 15: 158–165.

  23. 23.

    , , , , , et al. Multicomponent synthesis of antibacterial dihydropyridin and dihydropyran embelin derivatives. J Org Chem 2013; 78: 7977–7985.

  24. 24.

    , , , . Antioxidant activity and protection of pancreatic beta-cells by embelin in streptozotocin-induced diabetes. J Diabetes 2012; 4: 248–256.

  25. 25.

    , , , . Anti-diabetic activity of embelin: involvement of cellular inflammatory mediators, oxidative stress and other biomarkers. Phytomedicine 2013; 20: 797–804.

  26. 26.

    , , , , , . Insulin sensitization via partial agonism of PPARgamma and glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway by embelin in type 2 diabetic rats. Biochim Biophys Acta 2013; 1830: 2243–2255.

  27. 27.

    , , , , . Embelin inhibits proliferation, induces apoptosis and alters gene expression profiles in breast cancer cells. Pharmacol Rep 2016; 68: 638–644.

  28. 28.

    , , . Embelin-Induced Apoptosis of Human Prostate Cancer Cells Is Mediated through Modulation of Akt and beta-Catenin Signaling. PLoS One 2015; 10: e0134760.

  29. 29.

    , , , , , et al. Embelin inhibits pancreatic cancer progression by directly inducing cancer cell apoptosis and indirectly restricting IL-6 associated inflammatory and immune suppressive cells. Cancer Lett 2014; 354: 407–416.

  30. 30.

    , , . Activation of p38/JNK pathway is responsible for embelin induced apoptosis in lung cancer cells: transitional role of reactive oxygen species. PLoS One 2014; 9: e87050.

  31. 31.

    , , , , , et al. Embelin suppresses STAT3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase PTEN. Cancer Lett 2011; 308: 71–80.

  32. 32.

    , , , . Synergism between NF-kappa B inhibitor, celastrol, and XIAP inhibitor, embelin, in an acute myeloid leukemia cell line, HL-60. J Cancer Res Ther 2016; 12: 155–160.

  33. 33.

    , , . Preventive effect of embelin from embelia ribes on lipid metabolism and oxidative stress in high-fat diet-induced obesity in rats. Planta Med 2012; 78: 651–657.

  34. 34.

    , . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001; 25: 402–408.

  35. 35.

    , , , , , et al. miR-30e reciprocally regulates the differentiation of adipocytes and osteoblasts by directly targeting low-density lipoprotein receptor-related protein 6. Cell Death Dis 2013; 4: e845.

  36. 36.

    , , , , , et al. Mitochondria-targeted dodecyltriphenylphosphonium (C12TPP) combats high-fat-diet-induced obesity in mice. Int J Obes 2016; 40: 1864–1874.

  37. 37.

    , , , , , et al. Obesity but not high-fat diet impairs lymphatic function. Int J Obes 2016; 40: 1582–1590.

  38. 38.

    , , , , , et al. miR-200a regulates Rheb-mediated amelioration of insulin resistance after duodenal-jejunal bypass. Int J Obes 2016; 40: 1222–1232.

  39. 39.

    , , , , , . Altered microbiota contributes to reduced diet-induced obesity upon cold exposure. Cell Metab 2016; 23: 1216–1223.

  40. 40.

    , , , , , et al. Gut microbiota orchestrates energy homeostasis during cold. Cell 2015; 163: 1360–1374.

  41. 41.

    , . Molecular pathways: fatty acid synthase. Clin Cancer Res 2015; 21: 5434–5438.

  42. 42.

    , , , , , et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med 2013; 19: 1649–1654.

  43. 43.

    , , , , . Stearoyl-CoA desaturase 1 is a key determinant of membrane lipid composition in 3T3-L1 adipocytes. PLoS One 2016; 11: e0162047.

  44. 44.

    , , , , , et al. Anti-tumor activity of the X-linked inhibitor of apoptosis (XIAP) inhibitor embelin in gastric cancer cells. Mol Cell Biochem 2014; 386: 143–152.

  45. 45.

    , , , , , et al. Embelin suppresses dendritic cell functions and limits autoimmune encephalomyelitis through the TGF-beta/beta-catenin and STAT3 signaling pathways. Mol Neurobiol 2014; 49: 1087–1101.

  46. 46.

    , . Wnt signaling and adipocyte lineage commitment. Cell Cycle 2008; 7: 1191–1196.

  47. 47.

    , , , . Wnt signaling, de novo lipogenesis, adipogenesis and ectopic fat. Oncotarget 2014; 5: 11000–11003.

  48. 48.

    , . The WNT inhibitor Dickkopf 1 and bone morphogenetic protein 4 rescue adipogenesis in hypertrophic obesity in humans. Diabetes 2012; 61: 1217–1224.

  49. 49.

    , , , , , et al. Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 2006; 21: 934–945.

Download references

Acknowledgements

This work was supported by Grant Nos. 81672116, 81472040 and 81271977 to Baoli Wang from Natural Science Foundation of China. Xiaoxia Li and Hairui Yuan were partially supported by Grant Nos. 81101596 and 81601864 from Natural Science Foundation of China. The work was also supported by an Open Grant from Key Lab of Hormones and Development (Ministry of Health).

Author information

Author notes

    • Y Gao
    •  & J Li

    These authors contributed equally to the work.

Affiliations

  1. Key Lab of Hormones and Development (Ministry of Health), Tianjin Key Lab of Metabolic Diseases, Metabolic Diseases Hospital and Institute of Endocrinology, Tianjin Medical University, Tianjin, China

    • Y Gao
    • , J Li
    • , X Xu
    • , Y Yang
    • , J Zhou
    •  & B Wang
  2. Department of Microbiology, Tianjin Medical University School of Basic Medical Sciences, Tianjin, China

    • S Wang
    • , L Zhang
    •  & X Li
  3. Department of Biochemistry, Tianjin University of Traditional Chinese Medicine School of Integrative Medicine, Tianjin, China

    • F Zheng
  4. 2011 Collaborative Innovation Center for Metabolic Diseases, Metabolic Diseases Hospital, Tianjin Medical University, Tianjin, China

    • B Wang

Authors

  1. Search for Y Gao in:

  2. Search for J Li in:

  3. Search for X Xu in:

  4. Search for S Wang in:

  5. Search for Y Yang in:

  6. Search for J Zhou in:

  7. Search for L Zhang in:

  8. Search for F Zheng in:

  9. Search for X Li in:

  10. Search for B Wang in:

Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to X Li or B Wang.

Supplementary information

Word documents

  1. 1.

    Supplementary Table 1

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/ijo.2017.35

Supplementary Information accompanies this paper on International Journal of Obesity website (http://www.nature.com/ijo)