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.

  • Article
  • Published:

Cloned mice have an obese phenotype not transmitted to their offspring

Nature Medicine volume 8, pages 262–267 (2002)Cite this article

Abstract

Mammalian cloning using somatic cells has been accomplished successfully in several species, and its potential basic, clinical and therapeutic applications are being pursued on many fronts. Determining the long-term effects of cloning on offspring is crucial for consideration of future application of the technique. Although full-term development of animals cloned from adult somatic cells has been reported, problems in the resulting progeny indicate that the cloning procedure may not produce animals that are phenotypically identical to their cell donor. We used a mouse model to take advantage of its short generation time and lifespan. Here we report that the increased body weight of cloned B6C3F1 female mice reflects an increase of body fat in addition to a larger body size, and that these mice share many characteristics consistent with obesity. We also show that the obese phenotype is not transmitted to offspring generated by mating male and female cloned mice.

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: Cloned and control mice.
Figure 2: Mouse body weights.
Figure 3: Food intake.
Figure 4: Effect of MTII and leptin on food intake.

Similar content being viewed by others

References

  1. Wilmut, I., Schnieke, A.E., McWhir, J., Kind, A.J. & Campbell, K.H. Viable offspring derived from fetal and adult mammalian cells. Nature 385, 810–813 (1997).

    Article  CAS  Google Scholar 

  2. Wakayama, T., Perry, A.C.F., Zuccotti, M., Johnson, K.R. & Yanagimachi, R. Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature 394, 369–374 (1998).

    Article  CAS  Google Scholar 

  3. Wakayama, T. & Yanagimachi, R. Cloning of male mice from adult tail-tip cells. Nature Genet. 22, 127–128 (1999).

    Article  CAS  Google Scholar 

  4. Kato, Y. et al. Eight calves cloned from somatic cells of a single adult. Science 282, 2095–2098 (1998).

    Article  CAS  Google Scholar 

  5. Galli, C., Duchi, R., Moor, R. & Lazzari, G. Mammalian leukocytes contain all the genetic information necessary for the development of a new individual. Cloning 1, 161–170 (1999).

    Article  CAS  Google Scholar 

  6. Wells, D.N., Misica, P.M. & Tervit, H.R. Production of cloned calves following nuclear transfer with cultured adult mural granulosa cells. Biol. Reprod. 4, 996–1005 (1999).

    Article  Google Scholar 

  7. Kubota, C. et al. Six cloned calves produced from adult fibroblast cells after long-term culture. Proc. Natl. Acad. Sci. USA 97, 990–995 (2000).

    Article  CAS  Google Scholar 

  8. Polejaeva, I.A. et al. Cloned pigs produced by nuclear transfer from adult somatic cells. Nature 407, 86–90 (2000).

    Article  CAS  Google Scholar 

  9. Coleman, A. Somatic cell nuclear transfer in mammals: progress and applications. Cloning 1, 185–200 (1999/2000).

    Article  Google Scholar 

  10. Prather, R.S., Kuholzer, B., Lai, L. & Park, K.-W. Changes in the structure of nuclei after transfer to oocytes. Cloning, 2,117–122 (2000).

    Article  CAS  Google Scholar 

  11. Solter D. Mammalian cloning: advances and limitations. Nature Rev. Genet., 1, 199–207 (2000).

    Article  CAS  Google Scholar 

  12. Tsunoda, Y. & Kato, Y. The recent progress on nuclear transfer in mammals. Zoolog. Sci. 17, 1177–1184 (2000).

    Article  CAS  Google Scholar 

  13. Wakayama, T. & Yanagimachi, R. Mouse cloning with nucleus donor cells of different age and type. Mol. Reprod. Dev. 58, 376–383 (2001).

    Article  CAS  Google Scholar 

  14. Yamazaki, Y. et al. Assessment of the developmental totipotency of neural cells in the cerebral cortex of mouse embryo by nuclear transfer. Proc. Natl. Acad. Sci. USA 98, 14022–14026 (2001).

    Article  CAS  Google Scholar 

  15. Yanagimachi, R. Cloning: experience from the mouse and other animals. Mol. Cell. Endocrinol. (in the press).

  16. Renard, J.P. et al. Lymphoid hypoplasia and somatic cloning. Lancet 353, 1489–1491 (1999).

    Article  CAS  Google Scholar 

  17. Ogura, A. et al. Production of male cloned mice from fresh, cultured, and cryopreserved immature sertoli cells. Biol. Reprod. 62, 1579–1584 (2000).

    Article  CAS  Google Scholar 

  18. Shiels, P.G. et al. Analysis of telomeres lengths in cloned sheep. Nature 399, 316–317 (1999).

    Article  CAS  Google Scholar 

  19. Evans, M.J. et al. Mitochondrial DNA genotypes in nuclear transfer-derived cloned sheep. Nature Genet. 23, 90 (1999).

    Article  CAS  Google Scholar 

  20. Wakayama, T. et al. Cloning of mice to six generations. Nature 407, 318–319 (2000).

    Article  CAS  Google Scholar 

  21. Lanza, R.P. et al. Extension of cell life-span and telomere length in animals cloned from senescent somatic cells. Science 288, 665–669 (2000).

    Article  CAS  Google Scholar 

  22. Steinborn, R. et al. Mitochondrial DNA heteroplasmy in cloned cattle produced by fetal and adult cell cloning. Nature Genet. 25, 255–257 (2000).

    Article  CAS  Google Scholar 

  23. Tian, X.C., Xu, J. & Yang, X. Normal telomere lengths found in cloned cattle. Nature Genet. 26, 272–273 (2000).

    Article  CAS  Google Scholar 

  24. Ohgane, J. et al. DNA methylation variation in cloned mice. Genesis 30, 45–50 (2001).

    Article  CAS  Google Scholar 

  25. Tamashiro, K.L.K., Wakayama, T., Blanchard, R.J., Blanchard, D.C. & Yanagimachi, R. Postnatal growth and behavioral development of mice cloned from adult cumulus cells. Biol. Reprod. 63, 328 (2000).

    Article  CAS  Google Scholar 

  26. Humpherys, D. et al. Epigenetic instability in ES cells and cloned mice. Science 293, 95–97 (2001).

    Article  CAS  Google Scholar 

  27. Eggan, K. et al. Hybrid vigor, fetal overgrowth, and viability of mice derived by nuclear cloning and tetraploid embryo complementation. Proc. Natl. Acad. Sci. USA 98, 6209–6214 (2001).

    Article  CAS  Google Scholar 

  28. Young, L.E., Sinclair, K.D. & Wilmut, I. Large offspring syndrome in cattle and sheep. Rev. Reprod. 3, 155–163 (1998).

    Article  CAS  Google Scholar 

  29. Young, L.E. et al. Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture. Nature Genet. 27, 153 (2001).

    Article  CAS  Google Scholar 

  30. Dulioust, E. et al. Long-term effects of embryo freezing in mice. Proc. Natl. Acad. Sci. USA 92, 589–593 (1995).

    Article  CAS  Google Scholar 

  31. Turturro, A. et al. Growth curves and survival characteristics of the animals used in the Biomarkers of Aging Program. J. Gerontol. 54, B492–501 (1999).

    Article  CAS  Google Scholar 

  32. The Jackson Laboratory. JAX Notes #468 442–444 (The Jackson Laboratory, Marketing Communications, Bar Harbor, Maine, 1997).

  33. Baguisi, A. et al. Production of goats by somatic cell nuclear transfer. Nature Biotechnol. 17, 456–461 (1999).

    Article  CAS  Google Scholar 

  34. Lanza, R.P. et al. Cloned cattle can be healthy and normal. Nature 294, 1893–1894 (2001).

    CAS  Google Scholar 

  35. Seeley, R.J. et al. Melanocortin receptors in leptin effects. Nature 390, 349 (1997).

    Article  CAS  Google Scholar 

  36. Woods, S.C., Seeley, R.J., Porte, D. & Schwartz, M.W. Signals that regulate food intake and energy homeostasis. Science 280, 1378 (1998).

    Article  CAS  Google Scholar 

  37. Schwartz, M.W., Woods, S.C., Porte, D., Seeley, R.J. & Baskin, D.G. Central nervous system control of food intake. Nature 404, 661–671 (2000).

    Article  CAS  Google Scholar 

  38. Walker, S.K., Hartwich, K.M. & Seamark, R.F. The production of unusually large offspring following embryo manipulation: concepts and challenges. Theriogenology 45, 111–120 (1996).

    Article  Google Scholar 

  39. Kikyo, N. & Wolffe, A.P. Reprogramming nuclei: insights from cloning, nuclear transfer and heterokaryons. J. Cell Sci. 113, 11–20 (2000).

    CAS  PubMed  Google Scholar 

  40. Eggan, K. et al. X-Chromosome inactivation in cloned mouse embryos. Science 290, 1578–1581 (2000).

    Article  CAS  Google Scholar 

  41. Inoue, K. et al. Faithful expression of imprinted genes in cloned mice. Science 295, 297 (2002).

    Article  CAS  Google Scholar 

  42. Young, L.E. & Fairburn, H.R. Improving the safety of embryo technologies: Possible role of genomic imprinting. Theriogenology 53, 627–648 (2000).

    Article  CAS  Google Scholar 

  43. Ensinck, J.W., Laschansky, E.C., Vogel, R.E. & D'Alessio, D.A. Effect of somtostatin-28 on dynamics of insulin secretion in perfused rat pancreas. Diabetes 40, 1163–1169 (1991).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Ellis, L.Y. Ma, T. Osada and K. Smith for their contributions to this study. This work was supported by National Institutes of Health grants DK-48061 to R.R.S. and DK-17844 to S.C.W., the Victoria S. and Bradley L. Geist Foundation, the Kosasa Family Foundation and grants from the Katherine and Harold Castle Foundation to R.Y. The Obesity Research Center at the University of Cincinnati is supported by Procter & Gamble.

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Kellie L.K. Tamashiro, Jennifer L. Lachey, Matthew D. Wortman, Randy J. Seeley, Stephen C. Woods & Randall R. Sakai

  2. Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    David A. D'Alessio

  3. Department of Anatomy and Reproductive Biology, Institute for Biogenesis Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA

    Kellie L.K. Tamashiro, Teruhiko Wakayama, Hidenori Akutsu, Yukiko Yamazaki & Ryuzo Yanagimachi

Authors
  1. Kellie L.K. Tamashiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Teruhiko Wakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hidenori Akutsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yukiko Yamazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jennifer L. Lachey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthew D. Wortman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Randy J. Seeley
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David A. D'Alessio
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stephen C. Woods
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ryuzo Yanagimachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Randall R. Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Randall R. Sakai.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tamashiro, K., Wakayama, T., Akutsu, H. et al. Cloned mice have an obese phenotype not transmitted to their offspring. Nat Med 8, 262–267 (2002). https://doi.org/10.1038/nm0302-262

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0302-262

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing