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Large, but not Small Sustained Tensile Strains Stimulate Adipogenesis in Culture

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Abstract

Understanding the mechanoresponsiveness of adipocytes and the characteristics of the mechanical stimuli that regulate adipogenesis is critically important in establishing knowledge in regard to the long-term effects of a sedentary lifestyle (or immobility in extreme medical conditions) as well as concerning obesity and related diseases. In this study we subjected 3T3-L1 preadipocytes cultured on elastic substrata to different levels of static equiaxial tensile strains within the physiological range, up to substrate tensile strain (STS) of 12%, while inducing differentiation in the cultures. Based on prior work which revealed that adipogenesis is accelerated in cultures subjected to STS of 12% by activating the mitogen-activated protein kinase kinase signaling pathway, we were specifically interested in identifying the STS levels which trigger this process. We hence monitored the production and accumulation of lipid droplets (LDs) using a non-destructive, image-processing-based method that we have previously developed, for a period of 4 weeks. The experimental data demonstrated accelerated adipogenesis in the cultures subjected to STS levels of 6%, 9%, and 12% with respect to cultures subjected to STS of 3% and (non-stretched) control cultures. This accelerated adipogenic response to the large sustained STS manifested in significantly larger numbers and greater sizes of LDs in the cultures that were stretched to large STS levels (p < 0.05), starting at approximately day 14 following induction of differentiation. Hence, indeed, there appears to be a certain tensile strain threshold, or domain—which is found within the physiological range—above which the responsiveness of adipocytes to sustained static stretching increases and is manifested in accelerated adipogenesis.

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Abbreviations

ANOVA:

analysis of variance

CSA:

cell stretching apparatus

DDW:

double distilled water

DM:

differentiation medium

DMSO:

dimethyl sulfoxide

ERK:

extracellular signal-regulated kinases

GM:

growth medium

LDs:

lipid droplets

MAPK:

mitogen-activated protein kinase

MEK:

mitogen-activated protein kinase kinase

PM:

plasma membrane

SM:

supporting medium

STS:

substrate tensile strain

References

  1. Arathuzik, G. G., and A. E. Goebel-Fabbri. Nutrition therapy and the management of obesity and diabetes: an update. Curr. Diab. Rep. 11:106–110, 2011.

    Article  PubMed  CAS  Google Scholar 

  2. Arner, P., and K. L. Spalding. Fat cell turnover in humans. Biochem. Biophys. Res. Commun. 396:101–104, 2010.

    Article  PubMed  CAS  Google Scholar 

  3. Azagury, D. E., and D. B. Lautz. Obesity overview: epidemiology, health and financial impact, and guidelines for qualification for surgical therapy. Gastrointest. Endosc. Clin. N. Am. 21:189–201, 2011.

    Article  PubMed  Google Scholar 

  4. Burger, E. H., and J. Klein-Nulend. Mechanotransduction in bone-role of the lacunocanalicular network. FASEB J. 13:S101–S112, 1999.

    PubMed  CAS  Google Scholar 

  5. Crossno, J. T., S. M. Majka, T. Grazia, R. G. Gill, and D. J. Klemm. Rosiglitazone promotes development of a novel adipocyte population from bone marrow-derived circulating progenitor cells. J. Clin. Invest. 116:3220–3228, 2006.

    Article  PubMed  CAS  Google Scholar 

  6. Furukawa, N., P. Ongusaha, W. J. Jahng, K. Araki, C. S. Choi, H. J. Kim, Y. H. Lee, K. Kaibuchi, B. B. Kahn, H. Masuzaki, J. K. Kim, S. W. Lee, and Y. B. Kim. Role of Rho-kinase in regulation of insulin action and glucose homeostasis. Cell Metab. 2:119–129, 2005.

    Article  PubMed  CAS  Google Scholar 

  7. Geddes, D. M., and R. S. Cardill, II. An in vitro model of neural trauma: device characterization and calcium response to mechanical stretch. J. Biomech. Eng. 123:247–255, 2001.

    Article  PubMed  CAS  Google Scholar 

  8. Gefen, A., and M. Be’ery-Lipperman. Contribution of muscular weakness on osteoporosis: computational and animal models. Clin. Biomech. 20:984–997, 2005.

    Article  Google Scholar 

  9. Grandolfo, M., A. Calabrese, and P. D’Andrea. Mechanism of mechanically induced intercellular calcium waves in rabbit articular chondrocytes and in HIG-82 synovial cells. J. Bone Miner. Res. 13:443–453, 1998.

    Article  PubMed  CAS  Google Scholar 

  10. Gregoire, F. M., C. M. Smas, and H. S. Sook. Understanding adipocytes differentiation. Physiol. Rev. 78(3):783–809, 1998.

    PubMed  CAS  Google Scholar 

  11. Hara, Y., S. Wakino, Y. Tanabe, M. Saito, H. Tokuyama, N. Washida, S. Tatematsu, K. Yoshioka, K. Homma, K. Hasegawa, H. Minakuchi, K. Fujimura, K. Hosoya, K. Hayashi, K. Nakayama, and H. Itoh. Rho and Rho-kinase activity in adipocytes contributes to a vicious cycle in obesity that may involve mechanical stretch. Sci. Signal. 4:157 ra3, 2011.

    Article  Google Scholar 

  12. Hossain, M. G., T. Iwata, N. Mizusawa, S. W. Shima, T. Okutsu, K. Ishimoto, and K. Ypshimoto. Compressive force inhibits adipogenesis through COX-2-mediated down-regulation of PPARgamma2 and C/EBPalpha. J. Biosci. Bioeng. 109:297–303, 2010.

    Article  PubMed  CAS  Google Scholar 

  13. Huang, S. C., T. C. Wu, H. C. Yu, M. R. Chen, C. M. Liu, and W. S. Chiang. Mechanical strain modulates age-related changes in the proliferation and differentiation of mouse adipose-derived stromal cells. BMC Cell Biol. 10:11–18, 2010.

    Google Scholar 

  14. Jaalouk, D. E., and J. Lammerding. Mechanotransduction gone awry. Nat. Rev. Mol. Cell Biol. 10:63–73, 2009.

    Article  PubMed  CAS  Google Scholar 

  15. Jacobs, C. R., S. Temiyasathit, and A. B. Castillo. Osteocyte mechanobiology and pericellular mechanics. Annu. Rev. Biomed. Eng. 12:369–400, 2010.

    Article  PubMed  CAS  Google Scholar 

  16. Kato, H., H. Suga, H. Eto, J. Araki, N. Aoi, K. Doi, T. Iida, Y. Tabata, and K. Yoshimura. Reversible adipose tissue enlargement induced by external tissue suspension: possible contribution of basic fibroblast growth factor in the preservation of enlarged tissue. Tissue Eng. Part A 16(6):2029–2040, 2010.

    Article  PubMed  CAS  Google Scholar 

  17. Lee, A. A., T. Delhaas, L. K. Waldman, D. A. MackKenna, F. J. Villarreal, and A. D. McCulloch. An equibiaxial strain system for cultured cells. Am. J. Physiol. Cell Physiol. 271:1400–1408, 1996.

    Google Scholar 

  18. Linder-Ganz, E., N. Shabshin, Y. Itzchak, and A. Gefen. Assessment of mechanical conditions in sub-dermal tissues during sitting: a combined experimental-MRI and finite element approach. J. Biomech. 40:1443–1454, 2007.

    Article  PubMed  Google Scholar 

  19. Linder-Ganz, E., N. Shabshin, Y. Itzchak, Z. Yizhar, I. Siev-Ner, and A. Gefen. Strains and stresses in sub-dermal tissues of the buttocks are greater in paraplegics than in healthy during sitting. J. Biomech. 41:567–580, 2008.

    Article  PubMed  Google Scholar 

  20. Or-Tzadikario, S., R. Sopher, and A. Gefen. Quantitative monitoring of lipid accumulation over time in cultured adipocytes as function of culture conditions: toward controlled adipose tissue engineering. Tissue Eng. 16:1167–1181, 2010.

    Article  CAS  Google Scholar 

  21. Prusty, D., B. Park, K. E. Davis, and S. R. Farmer. Activation of MEK/ERK signaling promotes adipogenesis by enhancing peroxisome proliferator-activated receptor # (PPAR#) and C/EBPα gene expression during the differentiation of 3T3-L1 preadipocytes. J. Biol. Chem. 277:46226–46232, 2002.

    Article  PubMed  CAS  Google Scholar 

  22. Ramirez-Zacarias, J., F. Castro-Munozledo, and W. Kuri-Harcuch. Quantitation of adipose conversion and triglycerides by staining intracytoplasmic lipids with Oil red O. Histochemistry 97:493–497, 1992.

    Article  PubMed  CAS  Google Scholar 

  23. Rubin, C. T., E. Capilla, Y. K. Luu, B. Busa, H. Crawford, D. J. Nolan, V. Mittal, C. J. Rosen, J. E. Pessin, and S. Judex. Adipogenesis is inhibited by brief, daily exposure to high-frequency, extremely low-magnitude mechanical signals. Proc. Natl Acad. Sci. USA 104:17879–17884, 2010.

    Article  Google Scholar 

  24. Sadoshima, J., and S. Izumo. The cellular and molecular response of cardiac myocytes to mechanical stress. Annu. Rev. Physiol. 59:551–571, 1997.

    Article  PubMed  CAS  Google Scholar 

  25. Shabshin, N., V. Ougortsin, G. Zoizner, and A. Gefen. Evaluation of the effect of trunk tilt on compressive soft tissue deformations under the ischial tuberosities using weight-bearing MRI. Clin. Biomech. 25:402–408, 2010.

    Article  Google Scholar 

  26. Shabshin, N., G. Zoizner, A. Herman, V. Ougortsin, and A. Gefen. Use of weight-bearing MRI for evaluating wheelchair cushions based on internal soft-tissue deformations under ischial tuberosities. J. Rehabil. Res. Dev. 47:31–42, 2010.

    Article  PubMed  Google Scholar 

  27. Shoham, N., and A. Gefen. Mechanotransduction in adipocytes. J. Biomech. doi:10.1016/j.jbiomech.2011.10.023.

  28. Shoham, N., R. Gottlieb, O. Sharabani-Yosef, U. Zaretsky, D. Benayahu, and A. Gefen. Static mechanical stretching accelerates lipid production in 3T3-L1 adipocytes by activating the MEK signaling pathway. Am. J. Physiol. Cell Physiol. doi:10.1152/ajpcell.00167.2011.

  29. Slomka, N., and A. Gefen. Relationship between strain levels and permeability of the plasma membrane in statically stretched myoblasts. Ann. Biomed. Eng., 2011. doi:10.1007/s10439-011-0423-1.

  30. Slomka, N., S. Or-Tzadikario, D. Sassun, and A. Gefen. Membrane-stretch-induced cell death in deep tissue injury: computer model studies. Cell Mol. Bioeng. 2:118–132, 2009.

    Article  CAS  Google Scholar 

  31. Sopher, R., J. Nixon, C. Gorecki, and A. Gefen. Effects of intramuscular fat infiltration, scarring, and spasticity on the risk for sitting-acquired deep tissue injury in spinal cord injury patients. J. Biomech. Eng. 133:021011, 2011.

    Article  PubMed  Google Scholar 

  32. Tanabe, Y., M. Koga, M. Saito, Y. Matsunaga, and K. Nakayama. Inhibition of adipocyte differentiation by mechanical stretching through ERK-mediated downregulation of PPARgamma2. J. Cell Sci. 117:3605–3614, 2004.

    Article  PubMed  CAS  Google Scholar 

  33. Tanabe, Y., Y. Matsunaga, M. Saito, and K. Nakayama. Involvement of cyclooxygenase-2 in synergistic effect of cyclic stretching and eicosapentaenoic acid on adipocyte differentiation. J. Pharmacol. Sci. 106:478–484, 2008.

    Article  PubMed  CAS  Google Scholar 

  34. Turner, N. J., H. S. Jones, J. E. Davies, and A. E. Canfield. Cyclic stretch-induced TGFβ1/Smad signaling inhibits adipogenesis in umbilical cord progenitor cells. Biochem. Biophys. Res. Commun. 377:1147–1151, 2008.

    Article  PubMed  CAS  Google Scholar 

  35. Wang, J. H., and B. P. Thampatty. An introductory review of cell mechanobiology. Biomech. Model. Mechanobiol. 5:1–16, 2006.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research work is being supported by a grant from the Ministry of Science & Technology, Israel & the Ministry of Research, Taiwan (AG), and also, partially, by a grant from the Ela Kodesz Institute for Cardiac Physical Sciences and Engineering (AG).

Conflict of interest

The authors state that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, 69978, Tel Aviv, Israel

    Ayelet Levy, Sarit Enzer, Naama Shoham, Uri Zaretsky & Amit Gefen

Authors
  1. Ayelet Levy
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  2. Sarit Enzer
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  3. Naama Shoham
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  4. Uri Zaretsky
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  5. Amit Gefen
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Correspondence to Amit Gefen.

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Associate Editor Kent Leach oversaw the review of this article.

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Levy, A., Enzer, S., Shoham, N. et al. Large, but not Small Sustained Tensile Strains Stimulate Adipogenesis in Culture. Ann Biomed Eng 40, 1052–1060 (2012). https://doi.org/10.1007/s10439-011-0496-x

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  • DOI: https://doi.org/10.1007/s10439-011-0496-x

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