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Adaptive immune cells shape obesity-associated type 2 diabetes mellitus and less prominent comorbidities

Nature Reviews Endocrinology volume 18, pages 23–42 (2022)Cite this article

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Abstract

Obesity and type 2 diabetes mellitus (T2DM) are increasing in prevalence owing to decreases in physical activity levels and a shift to diets that include addictive and/or high-calorie foods. These changes are associated with the adoption of modern lifestyles and the presence of an obesogenic environment, which have resulted in alterations to metabolism, adaptive immunity and endocrine regulation. The size and quality of adipose tissue depots in obesity, including the adipose tissue immune compartment, are critical determinants of overall health. In obesity, chronic low-grade inflammation can occur in adipose tissue that can progress to systemic inflammation; this inflammation contributes to the development of insulin resistance, T2DM and other comorbidities. An improved understanding of adaptive immune cell dysregulation that occurs during obesity and its associated metabolic comorbidities, with an appreciation of sex differences, will be critical for repurposing or developing immunomodulatory therapies to treat obesity and/or T2DM-associated inflammation. This Review critically discusses how activation and metabolic reprogramming of lymphocytes, that is, T cells and B cells, triggers the onset, development and progression of obesity and T2DM. We also consider the role of immunity in under-appreciated comorbidities of obesity and/or T2DM, such as oral cavity inflammation, neuroinflammation in Alzheimer disease and gut microbiome dysbiosis. Finally, we discuss previous clinical trials of anti-inflammatory medications in T2DM and consider the path forward.

Key points

  • Although obesity and/or T2DM are widely known as metabolic diseases, the development of the field of meta-inflammation has demonstrated the strong immune component of both conditions.

  • An appropriate balance between T helper 17 cells and regulatory T cells, and effector and regulatory B cells, is essential to maintain local immunity during systemic inflammation, especially in obesity and in its associated comorbidities.

  • Clinical trials targeting inflammatory mediators of obesity and T2DM (such as IL-1β and tumour necrosis factor) to improve glycaemic control in T2DM have shown only moderate effects, suggesting that alternative sources of inflammation are important.

  • Consideration of sex-driven differences in adaptive immunity and adipose tissue function during obesity and/or T2DM-associated diseases will be critical to optimize treatment on an individualized basis.

  • Identification of shared activation markers between insulin-sensitive cells and tissue-resident or infiltrating pro-inflammatory immune cells will be important for a more complete understanding of obesity, T2DM and associated comorbidities.

  • T2DM-associated changes in adaptive immunity should be investigated for future clinical trials in T2DM; such knowledge will redirect the current focus on plasma cytokines to target development of new therapeutic approaches.

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Fig. 1: Insulin signalling in activated T cells favours the expansion of effector T cells over Treg cells.
Fig. 2: Adipocyte leptin promotes lymphocyte activation and TH17 cell differentiation.
Fig. 3: Calcium signalling upon T cell receptor or B cell receptor activation.
Fig. 4: Insulin resistance in the brain during neuroinflammation.
Fig. 5: Taste perception in taste bud cells is subject to immunoregulation.

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Acknowledgements

The authors acknowledge the support of R01DK108056 (B.S.N.), U01DE025383 (B.S.N.), R56AG069685 (B.S.N.), R01NS103785 (A.D.B.) and the TRIAD 5T32AG057461 (J.L.).

Review criteria

Full text articles were chosen using PubMed and Google scholar searches both using general terms such as ‘diabetes’, ‘obesity’, ‘adaptive immunity’, ‘T and B cells’, ‘comorbidities’, ‘inflammation’ and ‘metabolic reprograming’. We focused the research on articles from 2010–2020 but always including earlier publications historically relevant for the topic. Articles were full-text, English-language papers.

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Authors and Affiliations

  1. Department of Pharmacology and Nutritional Sciences and the Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA

    Sara SantaCruz-Calvo, Raji Rajesh Lenin, Beibei Zhu & Barbara S. Nikolajczyk

  2. Department of Nutrition and Public Health, Merrimack College, North Andover, MA, USA

    Leena Bharath

  3. Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, USA

    Gabriella Pugh

  4. Department of Chemistry and Food Technology, Technical University of Madrid, Madrid, Spain

    Lucia SantaCruz-Calvo

  5. Department of Neuroscience, University of Kentucky, Lexington, KY, USA

    Jenny Lutshumba & Adam D. Bachstetter

  6. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA

    Rui Liu

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  1. Sara SantaCruz-Calvo
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Contributions

B.S.N. and S.SC.C. contributed to all aspects of the preparation of the article. L.B. researched data for the article, contributed to discussion of the content and wrote the article. G.P., R.L. and A.D.B. researched data for the article and wrote the article. L.SC.C. researched data for the article and contributed to discussion of the content. R.R.L., J.L. and B.Z. researched data for the article.

Corresponding authors

Correspondence to Sara SantaCruz-Calvo or Barbara S. Nikolajczyk.

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The authors declare no competing interests.

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Nature Reviews Endocrinology thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Hormesis

An adaptive response of cells and organisms to a moderate stress.

Acetyl-CoA carboxylase

(ACC1). A rate-limiting enzyme in the synthesis of long-chain fatty acids.

Store-operated Ca2+ entry

(SOCE). A cellular mechanism enabling calcium shuttling from the extracellular space to the cytoplasm through the CRAC channels in the plasma membrane and STIM and STIM2 in the endoplasmic reticulum.

Blood–brain barrier

(BBB). A complex network of cells (endothelial cells, pericytes, astrocytes, microglial cells and neurons) that keep circulating blood cells, toxins or pathogens from entering the brain.

Toll-like receptor 4

(TLR4). Triggers tumour necrosis factor production in response to fatty acids and complexes with CD36 to recognize lipopolysaccharides.

Periodontal disease

Osteoclast-mediated destruction of the soft (gingival) and hard (bone) tooth-supporting structures, triggered by a combination of chronic inflammation and bacterial dysbiosis.

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SantaCruz-Calvo, S., Bharath, L., Pugh, G. et al. Adaptive immune cells shape obesity-associated type 2 diabetes mellitus and less prominent comorbidities. Nat Rev Endocrinol 18, 23–42 (2022). https://doi.org/10.1038/s41574-021-00575-1

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