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Cited by 1,370Adipokines, Inflammation, and Metabolic DiseasesT-cell and B-cell ImmunologyAdipose Tissue and Metabolism

Normalization of obesity-associated insulin resistance through immunotherapy

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Winer, Shawn, Chan, Yin, Paltser, Geoffrey, Truong, Dorothy, Tsui, Hubert, Bahrami, Jasmine, Dorfman, Ruslan, Wang, Yongqian +7 more·2009·Nature Medicine
DOI 10.1038/nm.2001PMC PMC3063199
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Abstract

Obesity and its associated metabolic syndromes represent a growing global challenge, yet mechanistic understanding of this pathology and current therapeutics are unsatisfactory. We discovered that CD4(+) T lymphocytes, resident in visceral adipose tissue (VAT), control insulin resistance in mice with diet-induced obesity (DIO). Analyses of human tissue suggest that a similar process may also occur in humans. DIO VAT-associated T cells show severely biased T cell receptor V(alpha) repertoires, suggesting antigen-specific expansion. CD4(+) T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon-gamma (IFN-gamma)-secreting T helper type 1 (T(H)1) cells, overwhelming static numbers of T(H)2 (CD4(+)GATA-binding protein-3 (GATA-3)(+)) and regulatory forkhead box P3 (Foxp3)(+) T cells. CD4(+) (but not CD8(+)) T cell transfer into lymphocyte-free Rag1-null DIO mice reversed weight gain and insulin resistance, predominantly through T(H)2 cells. In obese WT and ob/ob (leptin-deficient) mice, brief treatment with CD3-specific antibody or its F(ab')(2) fragment, reduces the predominance of T(H)1 cells over Foxp3(+) cells, reversing insulin resistance for months, despite continuation of a high-fat diet. Our data suggest that the progression of obesity-associated metabolic abnormalities is under the pathophysiological control of CD4(+) T cells. The eventual failure of this control, with expanding adiposity and pathogenic VAT T cells, can successfully be reversed by immunotherapy.

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  • VAT Treg cells have a documented unique transcriptome and T cell receptor (TCR) repertoire.

    “VAT Treg cells were analyzed due to their documented unique transcriptome and T cell receptor (TCR) repertoire, as well as their role in protecting from metabolic disease 22,33-36 .”

    From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [36]

    The Results section ('Fat-resident T cells'; page unavailable) reports a distinctive TCR repertoire in VAT T cells. But the cells in that analysis were not identified specifically as Tregs, and the paper does not document a unique VAT Treg transcriptome. Thus it supports only part of the attributed claim. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Treg cell immunosuppressive function plays a critical role in protecting HFD-fed mice (which do not progress to NASH) from developing insulin resistance.

    “Treg cell immunosuppressive function plays a critical role in protecting HFD-fed mice (which do not progress to NASH) from developing insulin resistance 22,36”

    From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [36]

    The Results (Immunotherapy of insulin resistance; page unavailable) report that treatment in HFD-fed mice restored visceral-fat Treg numbers and improved insulin sensitivity, but explicitly say this points to, rather than proves, a Treg-mediated effect. The Results (CD4+ T cells regulate obesity and glucose homeostasis; page unavailable) also find that metabolic improvement after CD4+ T-cell transfer did not require Treg function. The paper does not establish a critical protective role for Treg immunosuppression or address whether these mice progress to NASH. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Previous studies using Treg cell-transfer and -depletion models demonstrated a protective role for Treg cells in preventing insulin resistance in HFD feeding.

    “in contrast to previous studies which utilized Treg cell-transfer and -depletion models to demonstrate a protective role for Treg cells in preventing insulin resistance in the setting of HFD feeding 22,36”

    From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [36]

    The Results sections on immunotherapy report improved insulin sensitivity alongside restored visceral-fat Treg numbers in high-fat-diet mice, but say this points to, rather than proves, a Treg effect. In the CD4+ T-cell transfer experiments, Foxp3− cells improved metabolic measures as effectively as full grafts; the authors conclude that Treg function was not required in that model. This paper therefore does not demonstrate the claimed protective role through Treg-transfer and Treg-depletion models. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • VAT Treg cells have a role in protecting from metabolic disease.

    “VAT Treg cells were analyzed due to their documented unique transcriptome and T cell receptor (TCR) repertoire, as well as their role in protecting from metabolic disease 22,33-36 .”

    From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [36]

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Authors
Winer, S., Chan, Y., Paltser, G., Truong, D., Tsui, H., Bahrami, J., Dorfman, R., Wang, Y., Zielenski, J., Mastronardi, F., Maezawa, Y., Drucker, D. J., Engleman, E., Winer, D., & Dosch, H.-M.
Affiliations
  • University of Toronto (CA)
  • Mount Sinai Hospital (CA)
  • Stanford Medicine (US)
Corresponding author
Dosch, H.-Michael
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2009-07-26
Volume
15
Issue
8
Pages
921-929
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.2001
PMC
PMC3063199
OpenAlex
W2110630581
Cited by
1,370
References
8
Citations by year
2026: 35 · 2025: 46 · 2024: 64 · 2023: 51 · 2022: 64 · 2021: 82 · 2020: 74 · 2019: 71 · 2018: 77 · 2017: 95 · 2016: 89 · 2015: 105 · 2014: 102 · 2013: 138 · 2012: 96
FWCI
61.83
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
Canadian Institutes of Health Research (93749)
Topics
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
obesity, insulin resistance, CD4+ T cells, visceral adipose tissue, diet-induced obesity, Th1 cells, Th2 cells, regulatory T cells, Foxp3, interferon-gamma, T cell receptor repertoire, immunotherapy, leptin deficiency, glucose homeostasis, metabolic dysfunction
MeSH terms
Adipose Tissue, Animals, Cell Separation, Glucose, Homeostasis, Immunotherapy, Insulin Resistance, Mice, Inbred C57BL, Mice, Obese, Obesity, CD4-Positive T-Lymphocytes, Mice, Knockout, Homeodomain Proteins, Mice

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