Open Access

Isoimperatorin enhances 3T3‑L1 preadipocyte differentiation by regulating PPARγ and C/EBPα through the Akt signaling pathway

  • Authors:
    • Tiantuan Jiang
    • Xiaochen Shi
    • Zunqiang Yan
    • Xin Wang
    • Shuangbao Gun
  • View Affiliations

  • Published online on: July 26, 2019     https://doi.org/10.3892/etm.2019.7820
  • Pages: 2160-2166
  • Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lipodystrophic patients have an adipose tissue triglyceride storage defect that causes ectopic lipid accumulation, leading to severe insulin resistance. The present study investigated the potential role of isoimperatorin on 3T3‑L1 adipocyte differentiation. mRNA and protein levels of differentiation‑ and lipid accumulation‑associated genes, as well as the adipogenesis‑related signaling pathway were analyzed in control and isoimperatorin‑treated differentiated 3T3‑L1 adipocytes using reverse transcription‑quantitative PCR and western blot analysis. Results determined that isoimperatorin promoted 3T3‑L1 fibroblast adipogenesis in a dose‑dependent manner compared with standard differentiation inducers. Isoimperatorin significantly increased mRNA and protein expression of the crucial adipogenic transcription factors peroxisome proliferator activated receptor‑γ (PPARγ) and CCAAT enhancer binding protein‑α (C/EBPα). mRNA expression of the downstream adipogenesis‑related genes sterol regulatory element‑binding transcription factor 1c, adipocyte protein 2, fatty acid synthase, adiponectin and diacylglycerol O‑acyltransferase 2 were also significantly increased following isoimperatorin treatment. The underlying mechanism likely involved activation of the Akt signaling pathway. Taken together, the present findings indicated that isoimperatorin may alter PPARγ and C/EBPα expression via the Akt signaling pathway, resulting in promotion of adipogenesis. The results highlighted the potential use of isoimperatorin as a therapeutic agent for preventing diabetes.

References

1 

Petersen MC and Shulman GI: Mechanisms of insulin action and insulin resistance. Physiol Rev. 98:2133–2223. 2018. View Article : Google Scholar : PubMed/NCBI

2 

Samuel VT, Petersen KF and Shulman GI: Lipid-induced insulin resistance: Unravelling the mechanism. Lancet. 375:2267–2277. 2010. View Article : Google Scholar : PubMed/NCBI

3 

Virtue S and Vidal-Puig A: Adipose tissue expandability, lipotoxicity and the metabolic syndrome-an allostatic perspective. Biochim Biophys Acta. 1801:338–349. 2010. View Article : Google Scholar : PubMed/NCBI

4 

Scherer PE: Adipose tissue: From lipid storage compartment to endocrine organ. Diabetes. 55:1537–1545. 2006. View Article : Google Scholar : PubMed/NCBI

5 

Vatier C, Vantyghem M-C, Storey C, Jéru I, Christin-Maitre S, Fève B, Lascols O, Beltrand J, Carel JC, Vigouroux C and Bismuth E: Monogenic forms of lipodystrophic syndromes: Diagnosis, detection, and practical management considerations from clinical cases. Curr Med Res Opin. 35:543–552. 2019. View Article : Google Scholar : PubMed/NCBI

6 

Ghaben AL and Scherer PE: Adipogenesis and metabolic health. Nat Rev Mol Cell Biol. 20:242–258. 2019. View Article : Google Scholar : PubMed/NCBI

7 

Nawrocki AR and Scherer PE: Keynote review: The adipocyte as a drug discovery target. Drug Discov Today. 10:1219–1230. 2005. View Article : Google Scholar : PubMed/NCBI

8 

Rosen ED and MacDougald OA: Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol. 7:885–896. 2006. View Article : Google Scholar : PubMed/NCBI

9 

Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM and Mortensen RM: PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell. 4:611–617. 1999. View Article : Google Scholar : PubMed/NCBI

10 

Rosen ED, Walkey CJ, Puigserver P and Spiegelman BM: Transcriptional regulation of adipogenesis. Genes Dev. 14:1293–1307. 2000.PubMed/NCBI

11 

Xavier MN, Winter MG, Spees AM, den Hartigh AB, Nguyen K, Roux CM, Silva TM, Atluri VL, Kerrinnes T, Keestra AM, et al: PPAR gamma-mediated increase in glucose availability sustains chronic brucella abortus infection in alternatively activated macrophages. Cell Host Microbe. 14:159–170. 2013. View Article : Google Scholar : PubMed/NCBI

12 

Cristancho AG and Lazar MA: Forming functional fat: A growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol. 12:722–734. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Saltiel AR and Kahn CR: Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 414:799–806. 2001. View Article : Google Scholar : PubMed/NCBI

14 

Peng XD, Xu PZ, Chen ML, Hahn-Windgassen A, Skeen J, Jacobs J, Sundararajan D, Chen WS, Crawford SE, Coleman KG and Hay N: Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes Dev. 17:1352–1365. 2003. View Article : Google Scholar : PubMed/NCBI

15 

Rochford JJ: Mouse models of lipodystrophy and their significance in understanding fat regulation. Curr Top Dev Biol. 109:53–96. 2014. View Article : Google Scholar : PubMed/NCBI

16 

Sun NN, Wu TY and Chau CF: Natural dietary and herbal products in anti-obesity treatment. Molecules. 21:13512016. View Article : Google Scholar

17 

Wang S, Chen Q and He L: Development and validation of a gas chromatography-mass spectrometry method for the determination of isoimperatorin in rat plasma and tissue: Application to the pharmacokinetic and tissue distribution study. J Chromatogr B Analyt Technol Biomed Life Sci. 852:473–478. 2007. View Article : Google Scholar : PubMed/NCBI

18 

Shi X, Liu M, Zhang M, Zhang K, Liu S, Qiao S, Shi R, Jiang X and Wang Q: Identification of in vitro and in vivo metabolites of isoimperatorin using liquid chromatography/mass spectrometry. Food Chem. 141:357–365. 2013. View Article : Google Scholar : PubMed/NCBI

19 

Wijerathne CUB, Seo CS, Song JW, Park HS, Moon OS, Won YS, Kwon HJ and Son HY: Isoimperatorin attenuates airway inflammation and mucus hypersecretion in an ovalbumin-induced murine model of asthma. Int Immunopharmacol. 49:67–76. 2017. View Article : Google Scholar : PubMed/NCBI

20 

Hwang YH, Yang HJ and Ma JY: Simultaneous determination of three furanocoumarins by UPLC/MS/MS: Application to pharmacokinetic study of Angelica dahurica radix after oral administration to normal and experimental Colitis-induced rats. Molecules. 22:E4162017. View Article : Google Scholar : PubMed/NCBI

21 

Yang HB, Gao HR, Ren YJ, Fang FX, Tian HT, Gao ZJ, Song W, Huang SM and Zhao AF: Effects of isoimperatorin on proliferation and apoptosis of human gastric carcinoma cells. Oncol Lett. 15:7993–7998. 2018.PubMed/NCBI

22 

Pokharel YR, Han EH, Kim JY, Oh SJ, Kim SK, Woo ER, Jeong HG and Kang KW: Potent protective effect of isoimperatorin against aflatoxin B1-inducible cytotoxicity in H4IIE cells: Bifunctional effects on glutathione S-transferase and CYP1A. Carcinogenesis. 27:2483–2490. 2006. View Article : Google Scholar : PubMed/NCBI

23 

Wang LY, Cheng KC, Li Y, Niu CS, Cheng JT and Niu HS: The dietary furocoumarin imperatorin increases plasma GLP-1 levels in type 1-like diabetic rats. Nutrients. 9:E11922017. View Article : Google Scholar : PubMed/NCBI

24 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

25 

Tang QQ and Lane MD: Adipogenesis: From stem cell to adipocyte. Annu Rev Biochem. 81:715–736. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Zhang JW, Tang QQ, Vinson C and Lane MD: Dominant-negative C/EBP disrupts mitotic clonal expansion and differentiation of 3T3-L1 preadipocytes. Proc Natl Acad Sci USA. 101:43–47. 2004. View Article : Google Scholar : PubMed/NCBI

27 

Park M, Choi YA, Lee HG, Kim KI, Lim JS, Lee MS, Oh KS and Yang Y: Dephosphorylation of CCAAT/enhancer-binding protein beta by protein phosphatase 2A containing B56 delta is required at the early time of adipogenesis. Biochim Biophys Acta. 1841:1608–1618. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Cao H, Zhang S, Shan S, Sun C, Li Y, Wang H, Yu S, Liu Y, Guo F, Zhai Q, et al: Ligand-dependent corepressor (LCoR) represses the transcription factor C/EBP during early adipocyte differentiation. J Biol Chem. 292:18973–18987. 2017. View Article : Google Scholar : PubMed/NCBI

29 

Tang QQ and Lane MD: Activation and centromeric localization of CCAAT/enhancer-binding proteins during the mitotic clonal expansion of adipocyte differentiation. Genes Dev. 13:2231–2241. 1999. View Article : Google Scholar : PubMed/NCBI

30 

Morrison RF and Farmer SR: Role of PPARgamma in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18(INK4c) and p21(Waf1/Cip1), during adipogenesis. J Biol Chem. 274:17088–17097. 1999. View Article : Google Scholar : PubMed/NCBI

31 

Weisiger RA: Cytosolic fatty acid binding proteins catalyze two distinct steps in intracellular transport of their ligands. Mol Cell Biochem. 239:35–43. 2002. View Article : Google Scholar : PubMed/NCBI

32 

Rosen ED, Hsu CH, Wang X, Sakai S, Freeman MW, Gonzalez FJ and Spiegelman B: C/EBPalpha induces adipogenesis through PPARgamma: A unified pathway. Genes Dev. 16:22–26. 2002. View Article : Google Scholar : PubMed/NCBI

33 

Gonzalez FJ: Getting fat: Two new players in molecular adipogenesis. Cell Metab. 1:85–86. 2005. View Article : Google Scholar : PubMed/NCBI

34 

Mota de Sá P, Richard AJ, Hang H and Stephens JM: Transcriptional regulation of adipogenesis. Compr Physiol. 7:635–674. 2017. View Article : Google Scholar : PubMed/NCBI

35 

Wang Y, Viscarra J, Kim SJ and Sul HS: Transcriptional regulation of hepatic lipogenesis. Nat Rev Mol Cell Biol. 16:678–689. 2015. View Article : Google Scholar : PubMed/NCBI

36 

Moseti D, Regassa A and Kim WK: Molecular regulation of adipogenesis and potential anti-adipogenic bioactive molecules. Int J Mol Sci. 17:E1242016. View Article : Google Scholar : PubMed/NCBI

37 

Fan H, Dong W, Li Q, Zou X, Zhang Y, Wang J, Li S, Liu W, Dong Y, Sun H and Hou Z: Ajuba preferentially binds LXR alpha/RXR gamma heterodimer to enhance LXR target gene expression in liver cells. Mol Endocrinol. 29:1608–1618. 2015. View Article : Google Scholar : PubMed/NCBI

38 

Chen J, Zhou X, Wu W, Wang X and Wang Y: FTO-dependent function of N6-methyladenosine is involved in the hepatoprotective effects of betaine on adolescent mice. J Physiol Biochem. 71:405–413. 2015. View Article : Google Scholar : PubMed/NCBI

39 

Cases S, Smith SJ, Zheng YW, Myers HM, Lear SR, Sande E, Novak S, Collins C, Welch CB, Lusis AJ, et al: Identification of a gene encoding an acyl CoA: Diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc Natl Acad Sci USA. 95:13018–13023. 1998. View Article : Google Scholar : PubMed/NCBI

40 

Watt MJ and Steinberg GR: Regulation and function of triacylglycerol lipases in cellular metabolism. Biochem J. 414:313–325. 2008. View Article : Google Scholar : PubMed/NCBI

41 

Xu J and Liao K: Protein kinase B/AKT 1 plays a pivotal role in insulin-like growth factor-1 receptor signaling induced 3T3-L1 adipocyte differentiation. J Biol Chem. 279:35914–35922. 2004. View Article : Google Scholar : PubMed/NCBI

42 

Green CJ, Göransson O, Kular GS, Leslie NR, Gray A, Alessi DR, Sakamoto K and Hundal H: Use of Akt inhibitor and a drug-resistant mutant validates a critical role for protein kinase B/Akt in the insulin-dependent regulation of glucose and system A amino acid uptake. J Biol Chem. 283:27653–27667. 2008. View Article : Google Scholar : PubMed/NCBI

43 

Balakrishnan BB, Krishnasamy K and Choi KC: Moringa concanensis Nimmo ameliorates hyperglycemia in 3T3-L1 adipocytes by upregulating PPAR-gamma, C/EBP-alpha via Akt signaling pathway and STZ-induced diabetic rats. Biomed Pharmacother. 103:719–728. 2018. View Article : Google Scholar : PubMed/NCBI

44 

Choe WK, Kang BT and Kim SO: Water-extracted plum (Prunus salicina L. cv. Soldam) attenuates adipogenesis in murine 3T3-L1 adipocyte cells through the PI3K/Akt signaling pathway. Exp Ther Med. 15:1608–1615. 2018.PubMed/NCBI

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September 2019
Volume 18 Issue 3

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Copy and paste a formatted citation
APA
Jiang, T., Shi, X., Yan, Z., Wang, X., & Gun, S. (2019). Isoimperatorin enhances 3T3‑L1 preadipocyte differentiation by regulating PPARγ and C/EBPα through the Akt signaling pathway. Experimental and Therapeutic Medicine, 18, 2160-2166. https://doi.org/10.3892/etm.2019.7820
MLA
Jiang, T., Shi, X., Yan, Z., Wang, X., Gun, S."Isoimperatorin enhances 3T3‑L1 preadipocyte differentiation by regulating PPARγ and C/EBPα through the Akt signaling pathway". Experimental and Therapeutic Medicine 18.3 (2019): 2160-2166.
Chicago
Jiang, T., Shi, X., Yan, Z., Wang, X., Gun, S."Isoimperatorin enhances 3T3‑L1 preadipocyte differentiation by regulating PPARγ and C/EBPα through the Akt signaling pathway". Experimental and Therapeutic Medicine 18, no. 3 (2019): 2160-2166. https://doi.org/10.3892/etm.2019.7820