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:

Animal Models

Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity

International Journal of Obesity volume 44, pages 2419–2429 (2020)Cite this article

Subjects

Abstract

Background

Obesity is associated with impaired primary and secondary immune responses to influenza infection, with T cells playing a critical role. T-cell function is highly influenced by the cellular metabolic state; however, it remains unknown how altered systemic metabolism in obesity alters T-cell metabolism and function to influence immune response. Our objective was to identify the altered cellular metabolic state of T cells from obese mice so that we may target T-cell metabolism to improve immune response to infection.

Methods

Mice were fed normal chow or high-fat diet for 18–19 weeks. Changes in T-cell populations were analyzed in both adipose tissue and spleens using flow cytometry. Splenic T cells were further analyzed for nutrient uptake and extracellular metabolic flux. As changes in T-cell mitochondrial oxidation were observed in obesity, obese mice were treated with metformin for 6 weeks and compared to lean control mice or obese mice undergoing weight loss through diet switch; immunity was measured by survival to influenza infection.

Results

We found changes in T-cell populations in adipose tissue of high-fat diet-induced obese mice, characterized by decreased proportions of Treg cells and increased proportions of CD8+ T cells. Activated CD4+ T cells from obese mice had increased glucose uptake and oxygen consumption rate (OCR), compared to T cells from lean controls, indicating increased mitochondrial oxidation of glucose. Treatment of isolated CD4+ T cells with metformin was found to inhibit OCR in vitro and alter the expression of several activation markers. Last, treatment of obese mice with metformin, but not weight loss, was able to improve survival to influenza in obesity.

Conclusions

T cells from obese mice have an altered metabolic profile characterized by increased glucose oxidation, which can be targeted to improve survival against influenza infection.

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

Fig. 1: High-fat-diet-induced obese (DIO) mice have human obesity characteristics with no significant change in the proportions of peripheral T cells.
Fig. 2: Obesity is associated with changes in CD4+ T-cell metabolism.
Fig. 3: Obesity is associated with changes in CD4+ T-cell nutrient uptake.
Fig. 4: The antidiabetic drug metformin reverses T-cell metabolic dysfunction in CD4+ T cells and enhances memory markers.
Fig. 5: Metformin improves survival to influenza-infected obese mice independent of its effects on systemic metabolism.

Similar content being viewed by others

References

  1. Engin A. The definition and prevalence of obesity and metabolic syndrome. Adv Exp Med Biol. 2017;960:1–17.

    Article  CAS  Google Scholar 

  2. Pi-Sunyer X. The medical risks of obesity. Postgrad Med. 2009;121:21–33.

    Article  Google Scholar 

  3. Versini M, Jeandel PY, Rosenthal E, Shoenfeld Y. Obesity in autoimmune diseases: not a passive bystander. Autoimmun Rev. 2014;13:981–1000.

    Article  CAS  Google Scholar 

  4. Andersen CJ, Murphy KE, Fernandez ML. Impact of obesity and metabolic syndrome on immunity. Adv Nutr. 2016;7:66–75.

    Article  CAS  Google Scholar 

  5. Sell H, Habich C, Eckel J. Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol. 2012;8:709–16.

    Article  CAS  Google Scholar 

  6. Morgan OW, Bramley A, Fowlkes A, Freedman DS, Taylor TH, Gargiullo P, et al. Morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza A(H1N1) disease. PLoS ONE. 2010;5:e9694.

    Article  Google Scholar 

  7. Louie JK, Acosta M, Samuel MC, Schechter R, Vugia DJ, Harriman K, et al. A novel risk factor for a novel virus: obesity and 2009 pandemic influenza A (H1N1). Clin Infect Dis. 2011;52:301–12.

    Article  Google Scholar 

  8. Neidich SD, Green WD, Rebeles J, Karlsson EA, Schultz-Cherry S, Noah TL, et al. Increased risk of influenza among vaccinated adults who are obese. Int J Obes. 2017;41:1324–30.

    Article  CAS  Google Scholar 

  9. Sheridan PA, Paich HA, Handy J, Karlsson EA, Hudgens MG, Sammon AB, et al. Obesity is associated with impaired immune response to influenza vaccination in humans. Int J Obes. 2012;36:1072–7.

    Article  CAS  Google Scholar 

  10. Rebeles J, Green WD, Alwarawrah Y, Nichols AG, Eisner W, Danzaki K, et al. Obesity-induced changes in T-cell metabolism are associated with impaired memory T-cell response to influenza and are not reversed with weight loss. J Infect Dis. 2019;219:1652–61.

    Article  CAS  Google Scholar 

  11. Smith AG, Sheridan PA, Harp JB, Beck MA. Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus. J Nutr. 2007;137:1236–43.

    Article  CAS  Google Scholar 

  12. Smith AG, Sheridan PA, Tseng RJ, Sheridan JF, Beck MA. Selective impairment in dendritic cell function and altered antigen-specific CD8+ T-cell responses in diet-induced obese mice infected with influenza virus. Immunology. 2009;126:268–79.

    Article  CAS  Google Scholar 

  13. Green WD, Beck MA. Obesity impairs the adaptive immune response to influenza virus. Ann Am Thorac Soc. 2017;14 Suppl 5:S406–9.

    Article  Google Scholar 

  14. Ganeshan K, Chawla A. Metabolic regulation of immune responses. Annu Rev Immunol. 2014;32:609–34.

    Article  CAS  Google Scholar 

  15. Alwarawrah Y, Kiernan K, MacIver NJ. Changes in nutritional status impact immune cell metabolism and function. Front Immunol. 2018;9:1055.

    Article  Google Scholar 

  16. MacIver NJ, Michalek RD, Rathmell JC. Metabolic regulation of T lymphocytes. Annu Rev Immunol. 2013;31:259–83.

    Article  CAS  Google Scholar 

  17. Lochner M, Berod L, Sparwasser T. Fatty acid metabolism in the regulation of T cell function. Trends Immunol. 2015;36:81–91.

    Article  CAS  Google Scholar 

  18. Ma EH, Bantug G, Griss T, Condotta S, Johnson RM, Samborska B, et al. Serine is an essential metabolite for effector T cell expansion. Cell Metab. 2017;25:345–57.

    Article  CAS  Google Scholar 

  19. Ren W, Liao Y, Ding X, Jiang Y, Yan J, Xia Y, et al. Slc6a13 deficiency promotes Th17 responses during intestinal bacterial infection. Mucosal Immunol. 2019;12:531–44.

    Article  CAS  Google Scholar 

  20. Lee CF, Lo YC, Cheng CH, Furtmuller GJ, Oh B, Andrade-Oliveira V, et al. Preventing allograft rejection by targeting immune metabolism. Cell Rep. 2015;13:760–70.

    Article  CAS  Google Scholar 

  21. Milner JJ, Rebeles J, Dhungana S, Stewart DA, Sumner SC, Meyers MH, et al. Obesity increases mortality and modulates the lung metabolome during pandemic H1N1 influenza virus infection in mice. J Immunol. 2015;194:4846–59.

    Article  CAS  Google Scholar 

  22. Reed LJ, Muench H. A simple method of estimating fifty per cent endpoints. Am J Epidemiol. 1938;27:493–7.

    Article  Google Scholar 

  23. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60:1577–85.

    Article  CAS  Google Scholar 

  24. Paich HA, Sheridan PA, Handy J, Karlsson EA, Schultz-Cherry S, Hudgens MG, et al. Overweight and obese adult humans have a defective cellular immune response to pandemic H1N1 influenza A virus. Obesity. 2013;21:2377–86.

    Article  CAS  Google Scholar 

  25. Chapman NM, Boothby MR, Chi H. Metabolic coordination of T cell quiescence and activation. Nat Rev Immunol. 2020;20:55–70.

    Article  CAS  Google Scholar 

  26. Saucillo DC, Gerriets VA, Sheng J, Rathmell JC, Maciver NJ. Leptin metabolically licenses T cells for activation to link nutrition and immunity. J Immunol. 2014;192:136–44.

    Article  CAS  Google Scholar 

  27. Gerriets VA, Danzaki K, Kishton RJ, Eisner W, Nichols AG, Saucillo DC, et al. Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity. Eur J Immunol. 2016;46:1970–83.

    Article  CAS  Google Scholar 

  28. Pettersson US, Walden TB, Carlsson PO, Jansson L, Phillipson M. Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue. PloS ONE. 2012;7:e46057.

    Article  CAS  Google Scholar 

  29. Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC, Deoliveira D, et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 2014;20:61–72.

    Article  CAS  Google Scholar 

  30. Wieman HL, Wofford JA, Rathmell JC. Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking. Mol Biol Cell. 2007;18:1437–46.

    Article  CAS  Google Scholar 

  31. Wieman HL, Horn SR, Jacobs SR, Altman BJ, Kornbluth S, Rathmell JC. An essential role for the Glut1 PDZ-binding motif in growth factor regulation of Glut1 degradation and trafficking. Biochem J. 2009;418:345–67.

    Article  CAS  Google Scholar 

  32. Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science. 1996;272:60–6.

    Article  CAS  Google Scholar 

  33. Hengel RL, Thaker V, Pavlick MV, Metcalf JA, Dennis G Jr., Yang J, et al. Cutting edge: L-selectin (CD62L) expression distinguishes small resting memory CD4+ T cells that preferentially respond to recall antigen. J Immunol. 2003;170:28–32.

    Article  CAS  Google Scholar 

  34. Baaten BJ, Li CR, Bradley LM. Multifaceted regulation of T cells by CD44. Commun Integr Biol. 2010;3:508–12.

    Article  Google Scholar 

  35. Hufford MM, Kim TS, Sun J, Braciale TJ. The effector T cell response to influenza infection. Curr Top Microbiol Immunol. 2015;386:423–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Karlsson EA, Sheridan PA, Beck MA. Diet-induced obesity impairs the T cell memory response to influenza virus infection. J Immunol. 2010;184:3127–33.

    Article  CAS  Google Scholar 

Download references

Funding

This work was funded by NIH R01-DK106090, the Translating Duke Health: Controlling the Immune System Initiative, and the Derfner Foundation.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA

    Yazan Alwarawrah, Amanda G. Nichols, William Eisner, Jonathan Warren & Nancie J. MacIver

  2. Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA

    William D. Green & Melinda A. Beck

  3. Department of Immunology, Duke University School of Medicine, Durham, NC, USA

    Kaitlin Kiernan & Nancie J. MacIver

  4. Department of Pathology, Duke University School of Medicine, Durham, NC, USA

    Laura P. Hale

  5. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA

    Nancie J. MacIver

Authors
  1. Yazan Alwarawrah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amanda G. Nichols
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William D. Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William Eisner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kaitlin Kiernan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jonathan Warren
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Laura P. Hale
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Melinda A. Beck
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nancie J. MacIver
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nancie J. MacIver.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alwarawrah, Y., Nichols, A.G., Green, W.D. et al. Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity. Int J Obes 44, 2419–2429 (2020). https://doi.org/10.1038/s41366-020-00692-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-020-00692-3

This article is cited by

Search

Advanced search

Quick links