Retinoids Regulate Adipogenesis Involving the TGFβ/SMAD and Wnt/β-Catenin Pathways in Human Bone Marrow Mesenchymal Stem Cells

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2017 Apr 20

PMID 28420144

Citations 8

Authors

Jun Cao

Yuhong Ma

Weiqi Yao

Xiaoye Zhang

Dongcheng Wu

Affiliations

Soon will be listed here.

Abstract

Retinoids may regulate cell differentiation as ligands of retinoic acid receptors (RARs) and/or retinoid X receptors (RXRs). We showed that RAR agonists promoted adipogenesis by upregulating the expression of CCAAT/enhancer-binding protein β (C/EBPβ) in the early stages, but blocked adipogenesis at a later stage in human bone marrow mesenchymal stem cells (hBMSCs). RXR agonists promoted adipogenesis at all time points in hBMSCs. The effect of RAR agonists was mediated mainly by the RARβ subtype. RAR agonists, in contrast to RXR agonists, significantly promoted the expression of RARβ. Knockdown of the RARβ gene via small hairpin RNA (shRNA) attenuated the inhibition of RAR agonists toward adipogenesis. Furthermore, we found that RAR agonists upregulated the transforming growth factor β (TGFβ)/SMAD pathway and Wnt/β-catenin pathway on adipogenesis in hBMSCs, and the stimulating effects were noticeably decreased with the RARβ gene knockdown. Both RAR agonists and RXR agonists inhibited adipogenesis and blocked the promoter activity of C/EBPβ and peroxisome proliferator-activated receptor γ (PPARγ) in SW872 cell. These results indicated the RAR agonists perform dual roles in adipogenesis in hBMSCs, and the TGFβ/SMAD pathway and Wnt/β-catenin pathway may involve the inhibitory effect of RAR agonists. RARβ is the main receptor subtype mediating the effect. The roles of RXR agonists in adipogenesis exhibited cell type-specific differences, and may be based on the integration of signals from different RXR dimers.

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References

Petruschke T, Rohrig K, Hauner H . Transforming growth factor beta (TGF-beta) inhibits the differentiation of human adipocyte precursor cells in primary culture. Int J Obes Relat Metab Disord. 1994; 18(8):532-6. View

Bouchard F, Paquin J . Differential effects of retinoids and inhibitors of ERK and p38 signaling on adipogenic and myogenic differentiation of P19 stem cells. Stem Cells Dev. 2013; 22(14):2003-16. PMC: 3699902. DOI: 10.1089/scd.2012.0209. View

Nishizuka M, Koyanagi A, Osada S, Imagawa M . Wnt4 and Wnt5a promote adipocyte differentiation. FEBS Lett. 2008; 582(21-22):3201-5. DOI: 10.1016/j.febslet.2008.08.011. View

Lehmann J, Jong L, Fanjul A, Cameron J, Lu X, Haefner P . Retinoids selective for retinoid X receptor response pathways. Science. 1992; 258(5090):1944-6. DOI: 10.1126/science.1335166. View

Tang Q, Lane M . Adipogenesis: from stem cell to adipocyte. Annu Rev Biochem. 2012; 81:715-36. DOI: 10.1146/annurev-biochem-052110-115718. View

Sato M, Hiragun A, Mitsui H . Preadipocytes possess cellular retinoid binding proteins and their differentiation is inhibited by retinoids. Biochem Biophys Res Commun. 1980; 95(4):1839-45. DOI: 10.1016/s0006-291x(80)80113-6. View

van Zoelen E, Duarte I, Hendriks J, van der Woning S . TGFβ-induced switch from adipogenic to osteogenic differentiation of human mesenchymal stem cells: identification of drug targets for prevention of fat cell differentiation. Stem Cell Res Ther. 2016; 7(1):123. PMC: 5000485. DOI: 10.1186/s13287-016-0375-3. View

Sarjeant K, Stephens J . Adipogenesis. Cold Spring Harb Perspect Biol. 2012; 4(9):a008417. PMC: 3428766. DOI: 10.1101/cshperspect.a008417. View

Dave S, Nanduri R, Dkhar H, Bhagyaraj E, Rao A, Gupta P . Nuclear MEK1 sequesters PPARγ and bisects MEK1/ERK signaling: a non-canonical pathway of retinoic acid inhibition of adipocyte differentiation. PLoS One. 2014; 9(6):e100862. PMC: 4069188. DOI: 10.1371/journal.pone.0100862. View

10.

Garcia-Rojas P, Antaramian A, Gonzalez-Davalos L, Villarroya F, Shimada A, Varela-Echavarria A . Induction of peroxisomal proliferator-activated receptor gamma and peroxisomal proliferator-activated receptor gamma coactivator 1 by unsaturated fatty acids, retinoic acid, and carotenoids in preadipocytes obtained from bovine white adipose.... J Anim Sci. 2010; 88(5):1801-8. DOI: 10.2527/jas.2009-2579. View

11.

Santibanez J, Kocic J . Transforming growth factor-β superfamily, implications in development and differentiation of stem cells. Biomol Concepts. 2014; 3(5):429-45. DOI: 10.1515/bmc-2012-0015. View

12.

Gudas L, Wagner J . Retinoids regulate stem cell differentiation. J Cell Physiol. 2010; 226(2):322-30. PMC: 3315372. DOI: 10.1002/jcp.22417. View

13.

Liu Y, Liu Y, Zhang R, Wang X, Huang F, Yan Z . All-trans retinoic acid modulates bone morphogenic protein 9-induced osteogenesis and adipogenesis of preadipocytes through BMP/Smad and Wnt/β-catenin signaling pathways. Int J Biochem Cell Biol. 2013; 47:47-56. DOI: 10.1016/j.biocel.2013.11.018. View

14.

Zauberman A, Lapter S, Zipori D . Smad proteins suppress CCAAT/enhancer-binding protein (C/EBP) beta- and STAT3-mediated transcriptional activation of the haptoglobin promoter. J Biol Chem. 2001; 276(27):24719-25. DOI: 10.1074/jbc.M005813200. View

15.

Berry D, DeSantis D, Soltanian H, Croniger C, Noy N . Retinoic acid upregulates preadipocyte genes to block adipogenesis and suppress diet-induced obesity. Diabetes. 2012; 61(5):1112-21. PMC: 3331760. DOI: 10.2337/db11-1620. View

16.

Ijpenberg A, Tan N, Gelman L, Kersten S, Seydoux J, Xu J . In vivo activation of PPAR target genes by RXR homodimers. EMBO J. 2004; 23(10):2083-91. PMC: 424365. DOI: 10.1038/sj.emboj.7600209. View

17.

Sato M, Yajima Y, Kawashima S, Tanaka K, Kagechika H . Synergistic potentiation of thiazolidinedione-induced ST 13 preadipocyte differentiation by RAR synergists. Biochem Biophys Res Commun. 2001; 280(3):646-51. DOI: 10.1006/bbrc.2000.4172. View

18.

Demagny H, De Robertis E . Smad4/DPC4: A barrier against tumor progression driven by RTK/Ras/Erk and Wnt/GSK3 signaling. Mol Cell Oncol. 2016; 3(2):e989133. PMC: 4905428. DOI: 10.4161/23723556.2014.989133. View

19.

Monteiro M, Wdziekonski B, Villageois P, Vernochet C, Iehle C, Billon N . Commitment of mouse embryonic stem cells to the adipocyte lineage requires retinoic acid receptor beta and active GSK3. Stem Cells Dev. 2008; 18(3):457-63. DOI: 10.1089/scd.2008.0154. View

20.

Sagara C, Takahashi K, Kagechika H, Takahashi N . Molecular mechanism of 9-cis-retinoic acid inhibition of adipogenesis in 3T3-L1 cells. Biochem Biophys Res Commun. 2013; 433(1):102-7. DOI: 10.1016/j.bbrc.2013.02.057. View