Skip to main content
Springer Nature Link
Log in

Overexpression of TFAM Protects 3T3-L1 Adipocytes from NYGGF4 (PID1) Overexpression-Induced Insulin Resistance and Mitochondrial Dysfunction

  • Original Paper
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

NYGGF4, also known as phosphotyrosine interaction domain containing 1(PID1), is a recently discovered gene which is involved in obesity-related insulin resistance (IR) and mitochondrial dysfunction. We aimed to further elucidate the effects and mechanisms underlying NYGGF4-induced IR by investigating the effect of overexpressing mitochondrial transcription factor A (TFAM), which is essential for mitochondrial DNA transcription and replication, on NYGGF4-induced IR and mitochondrial abnormalities in 3T3-L1 adipocytes. Overexpression of TFAM increased the mitochondrial copy number and ATP content in both control 3T3-L1 adipocytes and NYGGF4-overexpressing adipocytes. Reactive oxygen species (ROS) production was enhanced in NYGGF4-overexpressing adipocytes and reduced in TFAM-overexpressing adipocytes; co-overexpression of TFAM significantly attenuated ROS production in NYGGF4-overexpressing adipocytes. However, overexpression of TFAM did not affect the mitochondrial transmembrane potential (ΔΨm) in control 3T3-L1 adipocytes or NYGGF4-overexpressing adipocytes. In addition, co-overexpression of TFAM-enhanced insulin-stimulated glucose uptake by increasing Glucose transporter type 4 (GLUT4) translocation to the PM in NYGGF4-overexpressing adipocytes. Overexpression of NYGGF4 significantly inhibited tyrosine phosphorylation of Insulin receptor substrate 1 (IRS-1) and serine phosphorylation of Akt, whereas overexpression of TFAM strongly induced phosphorylation of IRS-1 and Akt in NYGGF4-overexpressing adipocytes. This study demonstrates that NYGGF4 plays a role in IR by impairing mitochondrial function, and that overexpression of TFAM can restore mitochondrial function to normal levels in NYGGF4-overexpressing adipocytes via activation of the IRS-1/PI3K/Akt signaling pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  1. Jeffery, R. W., & Sherwood, N. E. (2008). Is the obesity epidemic exaggerated? No. British Medical Journal, 336(7638), 245.

    Article  PubMed  CAS  Google Scholar 

  2. Spiegelman, B. M., & Flier, J. S. (2001). Obesity and the regulation of energy balance. Cell, 104(4), 531–543.

    Article  PubMed  CAS  Google Scholar 

  3. Simoneau, J. A., & Kelley, D. E. (1997). Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in niddm. Journal of Applied Physiology, 83(1), 166–171.

    PubMed  CAS  Google Scholar 

  4. Zhang, C. M., Chen, X. H., Wang, B., Liu, F., Chi, X., Tong, M. L., et al. (2009). Over-expression of nyggf4 inhibits glucose transport in 3t3-l1 adipocytes via attenuated phosphorylation of irs-1 and akt. Acta Pharmacologica Sinica, 30(1), 120–124.

    Article  PubMed  Google Scholar 

  5. Zhao, Y., Zhang, C., Chen, X., Gao, C., Ji, C., Chen, F., et al. (2010). Overexpression of nyggf4 (pid1) induces mitochondrial impairment in 3t3-l1 adipocytes. Molecular and Cellular Biochemistry, 340(1–2), 41–48.

    Article  PubMed  CAS  Google Scholar 

  6. Petersen, K. F., Befroy, D., Dufour, S., Dziura, J., Ariyan, C., Rothman, D. L., et al. (2003). Mitochondrial dysfunction in the elderly: Possible role in insulin resistance. Science, 300(5622), 1140–1142.

    Article  PubMed  CAS  Google Scholar 

  7. Wang, B., Zhang, M., Ni, Y. H., Liu, F., Fan, H. Q., Fei, L., et al. (2006). Identification and characterization of nyggf4, a novel gene containing a phosphotyrosine-binding (ptb) domain that stimulates 3t3–l1 preadipocytes proliferation. Gene, 379, 132–140.

    Article  PubMed  CAS  Google Scholar 

  8. Qiu, J., Ni, Y. H., Gong, H. X., Fei, L., Pan, X. Q., Guo, M., et al. (2007). Identification of differentially expressed genes in omental adipose tissues of obese patients by suppression subtractive hybridization. Biochemical and Biophysical Research Communications, 352(2), 469–478.

    Article  PubMed  CAS  Google Scholar 

  9. Caratu, G., Allegra, D., Bimonte, M., Schiattarella, G. G., D’Ambrosio, C., Scaloni, A., et al. (2007). Identification of the ligands of protein interaction domains through a functional approach. Molecular and Cellular Proteomics, 6(2), 333–345.

    Article  PubMed  CAS  Google Scholar 

  10. Zhang, C. M., Zeng, X. Q., Zhang, R., Ji, C. B., Tong, M. L., Chi, X., et al. (2010). Effects of nyggf4 knockdown on insulin sensitivity and mitochondrial function in 3t3-l1 adipocytes. Journal of Bioenergetics and Biomembranes, 42(5), 433–439.

    Article  PubMed  CAS  Google Scholar 

  11. Wang, Y. M., Lin, X. F., Shi, C. M., Lu, L., Qin, Z. Y., Zhu, G. Z., et al. (2012). Alpha-lipoic acid protects 3t3-l1 adipocytes from nyggf4 (pid1) overexpression-induced insulin resistance through increasing phosphorylation of irs-1 and akt. Journal of Bioenergetics and Biomembranes, 44(3), 357–363.

    Article  PubMed  CAS  Google Scholar 

  12. Sawyer, D. E., Roman, S. D., & Aitken, R. J. (2001). Relative susceptibilities of mitochondrial and nuclear dna to damage induced by hydrogen peroxide in two mouse germ cell lines. Redox Report, 6(3), 182–184.

    Article  PubMed  CAS  Google Scholar 

  13. Abramova, N. E., Davies, K. J., & Crawford, D. R. (2000). Polynucleotide degradation during early stage response to oxidative stress is specific to mitochondria. Free Radical Biology and Medicine, 28(2), 281–288.

    Article  PubMed  CAS  Google Scholar 

  14. Fridlyand, L. E., & Philipson, L. H. (2006). Reactive species and early manifestation of insulin resistance in type 2 diabetes. Diabetes, Obesity and Metabolism, 8(2), 136–145.

    Article  PubMed  CAS  Google Scholar 

  15. Lee, H. K., Song, J. H., Shin, C. S., Park, D. J., Park, K. S., Lee, K. U., et al. (1998). Decreased mitochondrial DNA content in peripheral blood precedes the development of non-insulin-dependent diabetes mellitus. Diabetes Research and Clinical Practice, 42(3), 161–167.

    Article  PubMed  CAS  Google Scholar 

  16. Parisi, M. A., & Clayton, D. A. (1991). Similarity of human mitochondrial transcription factor 1 to high mobility group proteins. Science, 252(5008), 965–969.

    Article  PubMed  CAS  Google Scholar 

  17. Larsson, N. G., Wang, J., Wilhelmsson, H., Oldfors, A., Rustin, P., Lewandoski, M., et al. (1998). Mitochondrial transcription factor a is necessary for mtdna maintenance and embryogenesis in mice. Nature Genetics, 18(3), 231–236.

    Article  PubMed  CAS  Google Scholar 

  18. Kang, D., Kim, S. H., & Hamasaki, N. (2007). Mitochondrial transcription factor a (tfam): Roles in maintenance of mtdna and cellular functions. Mitochondrion, 7(1–2), 39–44.

    Article  PubMed  CAS  Google Scholar 

  19. Herz, J., & Strickland, D. K. (2001). Lrp: A multifunctional scavenger and signaling receptor. Journal Of Clinical Investigation, 108(6), 779–784.

    PubMed  CAS  Google Scholar 

  20. Kaaman, M., Sparks, L. M., van Harmelen, V., Smith, S. R., Sjolin, E., Dahlman, I., et al. (2007). Strong association between mitochondrial DNA copy number and lipogenesis in human white adipose tissue. Diabetologia, 50(12), 2526–2533.

    Article  PubMed  CAS  Google Scholar 

  21. Sundaresan, M., Yu, Z. X., Ferrans, V. J., Irani, K., & Finkel, T. (1995). Requirement for generation of h2o2 for platelet-derived growth factor signal transduction. Science, 270(5234), 296–299.

    Article  PubMed  CAS  Google Scholar 

  22. Woollacott, A. J., & Simpson, P. B. (2001). High throughput fluorescence assays for the measurement of mitochondrial activity in intact human neuroblastoma cells. Journal of Biomolecular Screening, 6(6), 413–420.

    Article  PubMed  CAS  Google Scholar 

  23. Ceddia, R. B., Somwar, R., Maida, A., Fang, X., Bikopoulos, G., & Sweeney, G. (2005). Globular adiponectin increases glut4 translocation and glucose uptake but reduces glycogen synthesis in rat skeletal muscle cells. Diabetologia, 48(1), 132–139.

    Article  PubMed  CAS  Google Scholar 

  24. Robin, E. D., & Wong, R. (1988). Mitochondrial DNA molecules and virtual number of mitochondria per cell in mammalian cells. Journal of Cellular Physiology, 136(3), 507–513.

    Article  PubMed  CAS  Google Scholar 

  25. Kang, D., & Hamasaki, N. (2002). Maintenance of mitochondrial DNA integrity: repair and degradation. Current Genetics, 41(5), 311–322.

    Article  PubMed  CAS  Google Scholar 

  26. Kang, D., & Hamasaki, N. (2005). Alterations of mitochondrial DNA in common diseases and disease states: Aging, neurodegeneration, heart failure, diabetes, and cancer. Current Medicinal Chemistry, 12(4), 429–441.

    Article  PubMed  CAS  Google Scholar 

  27. Park, S. Y., & Lee, W. (2007). The depletion of cellular mitochondrial DNA causes insulin resistance through the alteration of insulin receptor substrate-1 in rat myocytes. Diabetes Research and Clinical Practice, 77(Suppl 1), S165–S171.

    Article  PubMed  CAS  Google Scholar 

  28. Wu, W. L., Gan, W. H., Tong, M. L., Li, X. L., Dai, J. Z., Zhang, C. M., et al. (2011). Over-expression of nyggf4 (pid1) inhibits glucose transport in skeletal myotubes by blocking the irs1/pi3k/akt insulin pathway. Molecular Genetics and Metabolism, 102(3), 374–377.

    Article  PubMed  CAS  Google Scholar 

  29. Nishio, Y., Kanazawa, A., Nagai, Y., Inagaki, H., & Kashiwagi, A. (2004). Regulation and role of the mitochondrial transcription factor in the diabetic rat heart. Annals of the New York Academy of Sciences, 1011, 78–85.

    Article  PubMed  CAS  Google Scholar 

  30. Choi, Y. S., Kim, S., & Pak, Y. K. (2001). Mitochondrial transcription factor a (mttfa) and diabetes. Diabetes Research and Clinical Practice, 54(Suppl 2), S3–S9.

    Article  PubMed  CAS  Google Scholar 

  31. Kanazawa, A., Nishio, Y., Kashiwagi, A., Inagaki, H., Kikkawa, R., & Horiike, K. (2002). Reduced activity of mttfa decreases the transcription in mitochondria isolated from diabetic rat heart. American Journal of Physiology Endocrinology Metabolism, 282(4), E778–E785.

    PubMed  CAS  Google Scholar 

  32. Noack, H., Bednarek, T., Heidler, J., Ladig, R., Holtz, J., & Szibor, M. (2006). Tfam-dependent and independent dynamics of mtdna levels in c2c12 myoblasts caused by redox stress. Biochimica et Biophysica Acta, 1760(2), 141–150.

    Article  PubMed  CAS  Google Scholar 

  33. Bonnard, C., Durand, A., Peyrol, S., Chanseaume, E., Chauvin, M. A., Morio, B., et al. (2008). Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. Journal Of Clinical Investigation, 118(2), 789–800.

    PubMed  CAS  Google Scholar 

  34. Shadel, G. S., & Clayton, D. A. (1997). Mitochondrial DNA maintenance in vertebrates. Annual Review of Biochemistry, 66, 409–435.

    Article  PubMed  CAS  Google Scholar 

  35. Shutt, T. E., & Shadel, G. S. (2010). A compendium of human mitochondrial gene expression machinery with links to disease. Environmental and Molecular Mutagenesis, 51(5), 360–379.

    PubMed  CAS  Google Scholar 

  36. Lewis, S., Thomas, S. L., Hyde, J., Castle, D., Blood, R. W., & Komesaroff, P. A. (2010). “I don’t eat a hamburger and large chips every day!” a qualitative study of the impact of public health messages about obesity on obese adults. Bmc Public Health, 10, 309.

    Article  PubMed  Google Scholar 

  37. Kanzaki, M., & Pessin, J. E. (2003). Insulin signaling: glut4 vesicles exit via the exocyst. Current Biology, 13(14), R574–R576.

    Article  PubMed  CAS  Google Scholar 

  38. Saltiel, A. R., & Pessin, J. E. (2002). Insulin signaling pathways in time and space. Trends in Cell Biology, 12(2), 65–71.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Key Basic Research Program of China (2013CB530604) and the National Natural Science Foundation of China (Grant nos. 30973231 and 81270928), the Priority Academic Program Development of Jiangsu Higher Education Institutions (Grant no. 201104013), and the Talent Foundation of Jiangsu Province (Grant no. Hygiene-39). 2012 Graduate Student Innovation Project of Jiangsu province (Grant no. CXLX12_0559).

Author information

Authors and Affiliations

  1. State Key Laboratory of Reproductive Medicine, Department of Pediatrics, Nanjing Maternity and Child Health Hospital Affiliated to Nanjing Medical University, Nanjing, 210029, China

    Chun-Mei Shi, Guang-Feng Xu, Lei Yang, Zi-Yi Fu, Ling Chen, Ya-Hui Shen, Chen-Bo Ji & Xi-Rong Guo

  2. Institute of Pediatrics of Nanjing Medical University, Nanjing, 210029, China

    Chun-Mei Shi, Lei Yang, Ling Chen, Chen-Bo Ji & Xi-Rong Guo

  3. The 82th Hospital of the People’s Liberation Army, Huai’an, 223001, China

    Guang-Feng Xu & Hai-Long Fu

  4. School of Nursing, Nanjing Medical University, Nanjing, China

    Lu Zhu

Authors
  1. Chun-Mei Shi
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Guang-Feng Xu
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Lei Yang
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Zi-Yi Fu
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Ling Chen
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Hai-Long Fu
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Ya-Hui Shen
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Lu Zhu
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Chen-Bo Ji
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Xi-Rong Guo
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding authors

Correspondence to Chen-Bo Ji or Xi-Rong Guo.

Additional information

Chun-Mei Shi and Guang-Feng Xu contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shi, CM., Xu, GF., Yang, L. et al. Overexpression of TFAM Protects 3T3-L1 Adipocytes from NYGGF4 (PID1) Overexpression-Induced Insulin Resistance and Mitochondrial Dysfunction. Cell Biochem Biophys 66, 489–497 (2013). https://doi.org/10.1007/s12013-012-9496-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12013-012-9496-1

Keywords