Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Animal Models

Bone marrow mesenchymal stem cells of the intrauterine growth-restricted rat offspring exhibit enhanced adipogenic phenotype

International Journal of Obesity volume 40, pages 1768–1775 (2016)Cite this article

Subjects

Abstract

Objective:

Although intrauterine nutritional stress is known to result in offspring obesity and the metabolic phenotype, the underlying cellular/molecular mechanisms remain incompletely understood. We tested the hypothesis that compared with the controls, the bone marrow-derived mesenchymal stem cells (BMSCs) of the intrauterine growth-restricted (IUGR) offspring exhibit a more adipogenic phenotype.

Methods:

A well-established rat model of maternal food restriction (MFR), that is, 50% global caloric restriction during the later-half of pregnancy and ad libitum diet following birth that is known to result in an obese offspring with a metabolic phenotype was used. BMSCs at 3 weeks of age were isolated, and then molecularly and functionally profiled.

Results:

BMSCs of the intrauterine nutritionally-restricted offspring demonstrated an increased proliferation and an enhanced adipogenic molecular profile at miRNA, mRNA and protein levels, with an overall up-regulated PPARγ (miR-30d, miR-103, PPARγ, C/EPBα, ADRP, LPL, SREBP1), but down-regulated Wnt (LRP5, LEF-1, β-catenin, ZNF521 and RUNX2) signaling profile. Following adipogenic induction, compared with the control BMSCs, the already up-regulated adipogenic profile of the MFR BMSCs, showed a further increased adipogenic response.

Conclusions:

Markedly enhanced adipogenic molecular profile and increased cell proliferation of MFR BMSCs suggest a possible novel cellular/mechanistic link between the intrauterine nutritional stress and offspring metabolic phenotype. This provides new potential predictive and therapeutic targets against these conditions in the IUGR offspring.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Garver WS, Newman SB, Gonzales-Pacheco DM, Castillo JJ, Jelinek D, Heidenreich RA et al. The genetics of childhood obesity and interaction with dietary macronutrients. Genes Nutr 2013; 8: 271–287.

    Article  CAS  Google Scholar 

  2. Harding JE . The nutritional basis of the fetal origins of adult disease. Int J Epidemiol 2001; 30: 15–23.

    Article  CAS  Google Scholar 

  3. Barker DJ, Osmond C . Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986; 1: 1077–1081.

    Article  CAS  Google Scholar 

  4. Hales CN, Barker DJ . Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992; 35: 595–601.

    Article  CAS  Google Scholar 

  5. Tarantal AF, Berglund L . Obesity and lifespan health—importance of the fetal environment. Nutrients 2014; 6: 1725–1736.

    Article  CAS  Google Scholar 

  6. Martin RJ, Hausman GJ, Hausman DB . Regulation of adipose cell development in utero. Proc Soc Exp Biol Med 1998; 219: 200–210.

    Article  CAS  Google Scholar 

  7. Nombela-Arrieta C, Ritz J, Silberstein LE . The elusive nature and function of mesenchymal stem cells. Nat Rev Mol Cell Biol 2011; 12: 126–131.

    Article  CAS  Google Scholar 

  8. Lowe CE, O'Rahilly S, Rochford JJ . Adipogenesis at a glance. J Cell Sci 2011; 124: 2681–2686.

    Article  CAS  Google Scholar 

  9. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147.

    Article  CAS  Google Scholar 

  10. Tontonoz P, Hu E, Spiegelman BM . Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor gamma. Curr Opin Genet Dev 1995; 5: 571–576.

    Article  CAS  Google Scholar 

  11. Paek DS, Sakurai R, Saraswat A, Li Y, Khorram O, Torday JS et al. Metyrapone alleviates deleterious effects of maternal food restriction on lung development and growth of rat offspring. Reprod Sci 2015; 22: 207–222.

    Article  CAS  Google Scholar 

  12. Rehan VK, Li Y, Corral J, Saraswat A, Husain S, Dhar A et al. Metyrapone blocks maternal food restriction-induced changes in female rat offspring lung development. Reprod Sci 2014; 21: 517–525.

    Article  CAS  Google Scholar 

  13. Desai M, Gayle D, Babu J, Ross MG . Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition. Am J Physiol Regul Integr Comp Physiol 2005; 288: R91–R96.

    Article  CAS  Google Scholar 

  14. Desai M, Gayle D, Babu J, Ross MG . The timing of nutrient restriction during rat pregnancy/lactation alters metabolic syndrome phenotype. Am J Obstet Gynecol 2007; 196: 555–557.

    Article  Google Scholar 

  15. Karadag A, Sakurai R, Wang Y, Guo P, Desai M, Ross MG et al. Effect of maternal food restriction on fetal rat lung lipid differentiation program. Pediatr Pulmonol 2009; 44: 635–644.

    Article  Google Scholar 

  16. Tseng FW, Tsai MJ, Yu LY, Fu YS, Huang WC, Cheng H . Comparative effects of bone marrow mesenchymal stem cells on lipopolysaccharide-induced microglial activation. Oxid Med Cell Longev 2013; 2013: 234179.

    Article  Google Scholar 

  17. Miranda SC, Silva GA, Hell RC, Martins MD, Alves JB, Goes AM . Three-dimensional culture of rat BMMSCs in a porous chitosan-gelatin scaffold: A promising association for bone tissue engineering in oral reconstruction. Arch Oral Biol 2011; 56: 1–15.

    Article  CAS  Google Scholar 

  18. Hennrick KT, Keeton AG, Nanua S, Kijek TG, Goldsmith AM, Sajjan US et al. Lung cells from neonates show a mesenchymal stem cell phenotype. Am J Respir Crit Care Med 2007; 175: 1158–1164.

    Article  CAS  Google Scholar 

  19. Morales E, Sakurai R, Husain S, Paek D, Gong M, Ibe B et al. Nebulized PPARgamma agonists: a novel approach to augment neonatal lung maturation and injury repair in rats. Pediatr Res 2014; 75: 631–640.

    Article  CAS  Google Scholar 

  20. Sharbati-Tehrani S, Kutz-Lohroff B, Bergbauer R, Scholven J, Einspanier R . miR-Q: a novel quantitative RT-PCR approach for the expression profiling of small RNA molecules such as miRNAs in a complex sample. BMC. Mol Biol 2008; 9: 34.

    Google Scholar 

  21. Bilkovski R, Schulte DM, Oberhauser F, Gomolka M, Udelhoven M, Hettich MM et al. Role of WNT-5a in the determination of human mesenchymal stem cells into preadipocytes. J Biol Chem 2010; 285: 6170–6178.

    Article  CAS  Google Scholar 

  22. Christodoulides C, Lagathu C, Sethi JK, Vidal-Puig A . Adipogenesis and WNT signalling. Trends Endocrinol Metab 2009; 20: 16–24.

    Article  CAS  Google Scholar 

  23. Laudes M . Role of WNT signalling in the determination of human mesenchymal stem cells into preadipocytes. J Mol Endocrinol 2011; 46: R65–R72.

    CAS  PubMed  Google Scholar 

  24. Addison WN, Fu MM, Yang HX, Lin Z, Nagano K, Gori F et al. Direct transcriptional repression of Zfp423 by Zfp521 mediates a bone morphogenic protein-dependent osteoblast versus adipocyte lineage commitment switch. Mol Cell Biol 2014; 34: 3076–3085.

    Article  Google Scholar 

  25. Bialek P, Kern B, Yang X, Schrock M, Sosic D, Hong N et al. A twist code determines the onset of osteoblast differentiation. Dev Cell 2004; 6: 423–435.

    Article  CAS  Google Scholar 

  26. Muruganandan S, Roman AA, Sinal CJ . Adipocyte differentiation of bone marrow-derived mesenchymal stem cells: cross talk with the osteoblastogenic program. Cell Mol Life Sci 2009; 66: 236–253.

    Article  CAS  Google Scholar 

  27. Kobayashi H, Gao Y, Ueta C, Yamaguchi A, Komori T . Multilineage differentiation of Cbfa1-deficient calvarial cells in vitro. Biochem Biophys Res Commun 2000; 273: 630–636.

    Article  CAS  Google Scholar 

  28. Kang T, Lu W, Xu W, Anderson L, Bacanamwo M, Thompson W et al. MicroRNA-27 (miR-27) targets prohibitin and impairs adipocyte differentiation and mitochondrial function in human adipose-derived stem cells. J Biol Chem 2013; 288: 34394–34402.

    Article  CAS  Google Scholar 

  29. Gnanalingham MG, Mostyn A, Symonds ME, Stephenson T . Ontogeny and nutritional programming of adiposity in sheep: potential role of glucocorticoid action and uncoupling protein-2. Am J Physiol Regul Integr Comp Physiol 2005; 289: R1407–R1415.

    Article  CAS  Google Scholar 

  30. Tobi EW, Lumey LH, Talens RP, Kremer D, Putter H, Stein AD et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 2009; 18: 4046–4053.

    Article  CAS  Google Scholar 

  31. Desai M, Guang H, Ferelli M, Kallichanda N, Lane RH . Programmed upregulation of adipogenic transcription factors in intrauterine growth-restricted offspring. Reprod Sci 2008; 15: 785–796.

    Article  CAS  Google Scholar 

  32. Joss-Moore LA, Wang Y, Campbell MS, Moore B, Yu X, Callaway CW et al. Uteroplacental insufficiency increases visceral adiposity and visceral adipose PPARgamma2 expression in male rat offspring prior to the onset of obesity. Early Hum Dev 2010; 86: 179–185.

    Article  CAS  Google Scholar 

  33. Slawik M, Vidal-Puig AJ . Adipose tissue expandability and the metabolic syndrome. Genes Nutr 2007; 2: 41–45.

    Article  CAS  Google Scholar 

  34. Bluher M . Adipose tissue dysfunction contributes to obesity related metabolic diseases. Best Pract Res Clin Endocrinol Metab 2013; 27: 163–177.

    Article  Google Scholar 

  35. Oreffo RO, Lashbrooke B, Roach HI, Clarke NM, Cooper C . Maternal protein deficiency affects mesenchymal stem cell activity in the developing offspring. Bone 2003; 33: 100–107.

    Article  CAS  Google Scholar 

  36. Wu CL, Diekman BO, Jain D, Guilak F . Diet-induced obesity alters the differentiation potential of stem cells isolated from bone marrow, adipose tissue and infrapatellar fat pad: the effects of free fatty acids. Int J Obes (Lond) 2013; 37: 1079–1087.

    Article  CAS  Google Scholar 

  37. Nobili V, Alisi A, Panera N, Agostoni C . Low birth weight and catch-up-growth associated with metabolic syndrome: a ten year systematic review. Pediatr Endocrinol Rev 2008; 6: 241–247.

    PubMed  Google Scholar 

Download references

Acknowledgements

This research was funded by grants from the NIH (HD058948, HL107118, HD071731, HD127237) and the TRDRP (17RT-0170, and 23RT-0018). The authors had full access to all of the data and take responsibility for the integrity of the data and the accuracy of analysis.

Author contributions

VKR conceived this work. MG, SA, RS, and JL carried out the experiments. VKR, MG, RS, MI analyzed the data. VKR, MG and SA drafted the paper. All authors have the approval of the submitted work.

Author information

Author notes

  1. M Gong and S Antony: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Pediatrics, Neonatal Intensive Care Unit, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine, Torrance, CA, USA

    M Gong, S Antony, R Sakurai, J Liu, M Iacovino & V K Rehan

Authors
  1. M Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Antony
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Sakurai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Iacovino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. V K Rehan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V K Rehan.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gong, M., Antony, S., Sakurai, R. et al. Bone marrow mesenchymal stem cells of the intrauterine growth-restricted rat offspring exhibit enhanced adipogenic phenotype. Int J Obes 40, 1768–1775 (2016). https://doi.org/10.1038/ijo.2016.157

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2016.157

This article is cited by

Search

Advanced search

Quick links