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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

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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.

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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.

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Funding

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

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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
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Correspondence to Nancie J. MacIver.

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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

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