Insulin-sparing and fungible effects of E4orf1 combined with an adipocyte-targeting sequence in mouse models of type 1 and type 2 diabetes (original) (raw)

Animal Models

International Journal of Obesity volume 41, pages 1601–1605 (2017)Cite this article

Subjects

Abstract

Obesity impairs glycemic control and causes insulin resistance and type 2 diabetes. Adenovirus 36 (Ad36) infection can increase the uptake of excess glucose from blood into adipocytes by increasing GLUT4 translocation through the Ras–Akt signaling pathway, which bypasses PI3K–Akt-mediated insulin receptor signaling. E4orf1, a viral gene expressed early during Ad36 infection, is responsible for this insulin-sparing effect and may be an alternative target for improving insulin resistance. To deliver the gene to adipocytes only, we connected the adipocyte-targeting sequence (ATS) to the 5′ end of E4orf1 (ATS–E4orf1). In vitro transfection of ATS–E4orf1 into preadipocytes activated factors for GLUT4 translocation and adipogenesis to the same extent as did Hemagglutinin (HA)-E4orf1 transfection as positive reference. Moreover, the Transwell migration assay also showed that ATS–E4orf1 secreted by liver cells activated Akt in preadipocytes. We used a hydrodynamic gene delivery technique to deliver ATS–E4orf1 into high-fat diet-fed and streptozotocin-injected mice (disease models of type 2 and type 1 diabetes, respectively). ATS–E4orf1 improved the ability to eliminate excess glucose from the blood and ameliorated liver function in both disease models. These findings suggest that ATS–E4orf1 has insulin-sparing and fungible effects in type 2 and 1 diabetes independent of the presence of insulin.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

USD 39.95

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

Additional access options:

References

  1. NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants. Lancet 2016; 387: 1377–1396.
    Article Google Scholar
  2. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001; 86: 1930–1935.
    Article CAS Google Scholar
  3. Cadeddu C, Nocco S, Cugusi L, Deidda M, Fabio O, Bandino S et al. Effects of metformin and exercise training, alone or in combination, on cardiac function in individuals with insulin resistance. Cardiol Ther 2016; 5: 63–73.
    Article Google Scholar
  4. Krishnapuram R, Dhurandhar EJ, Dubuisson O, Kirk-Ballard H, Bajpeyi S, Butte N et al. Template to improve glycemic control without reducing adiposity or dietary fat. Am J Physiol Endocrinol Metab 2011; 300: E779–E789.
    Article CAS Google Scholar
  5. Wang ZQ, Cefalu WT, Zhang XH, Yu Y, Qin J, Son L et al. Human adenovirus type 36 enhances glucose uptake in diabetic and nondiabetic human skeletal muscle cells independent of insulin signaling. Diabetes 2008; 57: 1805–1813.
    Article CAS Google Scholar
  6. Krishnapuram R, Kirk-Ballard H, Dhurandhar EJ, Dubuisson O, Messier V, Rabasa-Lhoret R et al. Insulin receptor-independent upregulation of cellular glucose uptake. Int J Obes 2013; 37: 146–153.
    Article CAS Google Scholar
  7. Dhurandhar EJ, Dubuisson O, Mashtalir N, Krishnapuram R, Hegde V, Dhurandhar NV . E4orf1: a novel ligand that improves glucose disposal in cell culture. PLoS One 2011; 6: e23394.
    Article CAS Google Scholar
  8. Kusminski CM, Gallardo-Montejano VI, Wang ZV, Hegde V, Bickel PE, Dhurandhar NV et al. E4orf1 induction in adipose tissue promotes insulin-independent signaling in the adipocyte. Mol Metab 2015; 4: 653–664.
    Article CAS Google Scholar
  9. Na HN, Dubuisson O, Hegde V, Nam JH, Dhurandhar NV . Human adenovirus Ad36 and its E4orf1 gene enhance cellular glucose uptake even in the presence of inflammatory cytokines. Biochimie 2016; 124: 3–10.
    Article CAS Google Scholar
  10. Kolonin MG, Saha PK, Chan L, Pasqualini R, Arap W . Reversal of obesity by targeted ablation of adipose tissue. Nat Med 2004; 10: 625–632.
    Article CAS Google Scholar
  11. Won YW, Adhikary PP, Lim KS, Kim HJ, Kim JK, Kim YH . Oligopeptide complex for targeted non-viral gene delivery to adipocytes. Nat Mater 2014; 13: 1157–1164.
    Article CAS Google Scholar
  12. Suda T, Liu D . Hydrodynamic gene delivery: its principles and applications. Mol Ther 2007; 15: 2063–2069.
    Article CAS Google Scholar
  13. Nam JH, Na HN, Atkinson RL, Dhurandhar NV . Genomic stability of adipogenic human adenovirus 36. Int J Obes 2014; 8: 21–24.
    Google Scholar
  14. Cho A, Seok SH . Ethical guidelines for use of experimental animals in biomedical research. J Bacteriol Virol 2013; 43: 18–26.
    Article Google Scholar
  15. Kendall RT, Feghali-Bostwick CA . Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol 2014; 5: 123.
    Article Google Scholar
  16. Zhang Y, Wang X, Yang H, Liu H, Lu Y, Han L et al. Kinase AKT controls innate immune cell development and function. Immunology 2013; 140: 143–152.
    Article CAS Google Scholar
  17. Chang L, Chiang SH, Saltiel AR . Insulin signaling and the regulation of glucose transport. Mol Med 2004; 10: 65–71.
    Article CAS Google Scholar

Download references

Acknowledgements

This research was supported by a grant from the Korean Health Technology R&D Project through the Korea health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C2955 and HI13C0826), the KFDA (16172INFECTION268), and Basic Science Research Program through the NRF funded by the Ministry of Science, ICT & Future Planning (NRF-2015M3A9B5030157).

Author information

Authors and Affiliations

  1. Department of Biotechnology, The Catholic University of Korea, Bucheon, Republic of Korea
    I-S Yoon, S Park, R-H Kim, H L Ko & J-H Nam

Authors

  1. I-S Yoon
  2. S Park
  3. R-H Kim
  4. H L Ko
  5. J-H Nam

Corresponding author

Correspondence toJ-H Nam.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the International Journal of Obesity website

Supplementary information

Rights and permissions

About this article

Cite this article

Yoon, IS., Park, S., Kim, RH. et al. Insulin-sparing and fungible effects of E4orf1 combined with an adipocyte-targeting sequence in mouse models of type 1 and type 2 diabetes.Int J Obes 41, 1601–1605 (2017). https://doi.org/10.1038/ijo.2017.142

Download citation

This article is cited by