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

Publication ,  Journal Article
Alwarawrah, Y; Nichols, AG; Green, WD; Eisner, W; Kiernan, K; Warren, J; Hale, LP; Beck, MA; MacIver, NJ
Published in: Int J Obes (Lond)
December 2020

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.

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Published In

Int J Obes (Lond)

DOI

EISSN

1476-5497

Publication Date

December 2020

Volume

44

Issue

12

Start / End Page

2419 / 2429

Location

England

Related Subject Headings

  • Spleen
  • Oxidative Stress
  • Orthomyxoviridae Infections
  • Obesity
  • Mice, Inbred C57BL
  • Mice
  • Metformin
  • Influenza A Virus, H1N1 Subtype
  • Endocrinology & Metabolism
  • Diet, High-Fat
 

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Alwarawrah, Y., Nichols, A. G., Green, W. D., Eisner, W., Kiernan, K., Warren, J., … MacIver, N. J. (2020). Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity. Int J Obes (Lond), 44(12), 2419–2429. https://doi.org/10.1038/s41366-020-00692-3
Alwarawrah, Yazan, Amanda G. Nichols, William D. Green, William Eisner, Kaitlin Kiernan, Jonathan Warren, Laura P. Hale, Melinda A. Beck, and Nancie J. MacIver. “Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity.Int J Obes (Lond) 44, no. 12 (December 2020): 2419–29. https://doi.org/10.1038/s41366-020-00692-3.
Alwarawrah Y, Nichols AG, Green WD, Eisner W, Kiernan K, Warren J, et al. Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity. Int J Obes (Lond). 2020 Dec;44(12):2419–29.
Alwarawrah, Yazan, et al. “Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity.Int J Obes (Lond), vol. 44, no. 12, Dec. 2020, pp. 2419–29. Pubmed, doi:10.1038/s41366-020-00692-3.
Alwarawrah Y, Nichols AG, Green WD, Eisner W, Kiernan K, Warren J, Hale LP, Beck MA, MacIver NJ. Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity. Int J Obes (Lond). 2020 Dec;44(12):2419–2429.

Published In

Int J Obes (Lond)

DOI

EISSN

1476-5497

Publication Date

December 2020

Volume

44

Issue

12

Start / End Page

2419 / 2429

Location

England

Related Subject Headings

  • Spleen
  • Oxidative Stress
  • Orthomyxoviridae Infections
  • Obesity
  • Mice, Inbred C57BL
  • Mice
  • Metformin
  • Influenza A Virus, H1N1 Subtype
  • Endocrinology & Metabolism
  • Diet, High-Fat