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Emerging mechanisms of obesity-associated immune dysfunction

Nature Reviews Endocrinology volume 20, pages 136–148 (2024)Cite this article

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Abstract

Obesity is associated with a wide range of complications, including type 2 diabetes mellitus, cardiovascular disease, hypertension and nonalcoholic fatty liver disease. Obesity also increases the incidence and progression of cancers, autoimmunity and infections, as well as lowering vaccine responsiveness. A unifying concept across these differing diseases is dysregulated immunity, particularly inflammation, in response to metabolic overload. Herein, we review emerging mechanisms by which obesity drives inflammation and autoimmunity, as well as impairing tumour immunosurveillance and the response to infections. Among these mechanisms are obesity-associated changes in the hormones that regulate immune cell metabolism and function and drive inflammation. The cargo of extracellular vesicles derived from adipose tissue, which controls cytokine secretion from immune cells, is also dysregulated in obesity, in addition to impairments in fatty acid metabolism related to inflammation. Furthermore, an imbalance exists in obesity in the biosynthesis and levels of polyunsaturated fatty acid-derived oxylipins, which control a range of outcomes related to inflammation, such as immune cell chemotaxis and cytokine production. Finally, there is a need to investigate how obesity influences immunity using innovative model systems that account for the heterogeneous nature of obesity in the human population.

Key points

  • Obesity dysregulates immunity through differing mechanisms, which contribute to a range of secondary complications.

  • Obesity influences the level and function of nutritionally regulated hormones that regulate signalling pathways that mediate immune cell metabolism and function and drive inflammation.

  • Expansion of adipose tissue dysregulates the abundance and composition of extracellular vesicles, which carry a wide range of cargo that can affect the activity of immune cells and lipid metabolism.

  • Increased adiposity dysregulates polyunsaturated fatty acid metabolism; notably, the concentration of oxylipins synthesized from polyunsaturated fatty acids, which control a range of outcomes related to inflammation, is imbalanced in obesity.

  • Investigating immunity in obesity requires translation from inbred rodents to humans; one approach is to use Diverse Outbred and Collaborative Cross mouse populations that can model the heterogeneous nature of human obesity.

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Fig. 1: Summary of obesity-associated hormone signalling and the regulation of immunometabolism and immune function.
Fig. 2: Extracellular vesicles and their effect on immune functions.
Fig. 3: Molecular pathways by which select monohydroxy oxylipins synthesized from polyunsaturated fatty acids control immunological responses in obesity.
Fig. 4: Proposed mechanisms leading to obesity-associated immune dysfunction.

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Acknowledgements

The authors would like to acknowledge the support of NIH grant P30DK056350 (S.R.S.); NIH grant R01ES031378 (S.R.S.); and NIH grant R21CA253163 (N.J.M.).

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Authors and Affiliations

  1. Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Saame Raza Shaikh, Melinda A. Beck & Nancie J. MacIver

  2. Department of Paediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Yazan Alwarawrah & Nancie J. MacIver

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Contributions

M.A.B., S.R.S. and N.J.M. researched data for the article, contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. Y.A. contributed substantially to discussion of the content and wrote the article.

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Correspondence to Saame Raza Shaikh, Melinda A. Beck or Nancie J. MacIver.

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Competing interests

S.R.S. has received industry support from Wiley Companies and Metagenics for studies on n-3 and n-7 fatty acids and from Sanofi, Solutex and Wiley Companies for organizing conferences. N.J.M., Y.A. and M.A.B. declare no competing interests.

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Shaikh, S.R., Beck, M.A., Alwarawrah, Y. et al. Emerging mechanisms of obesity-associated immune dysfunction. Nat Rev Endocrinol 20, 136–148 (2024). https://doi.org/10.1038/s41574-023-00932-2

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