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Cited by 204Adipokines, Inflammation, and Metabolic DiseasesAcute Myeloid Leukemia ResearchMetabolism, Diabetes, and Cancer

TET2-loss-of-function-driven clonal hematopoiesis exacerbates experimental insulin resistance in aging and obesity

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Fuster, José J., Zuriaga, María A., Zorita, Virginia, MacLauchlan, Susan, Polackal, Maya N., Viana-Huete, Vanesa, Ferrer-Pérez, Alba, Matesanz, Nuria +5 more·2020·Cell Reports
DOI 10.1016/j.celrep.2020.108326PMC PMC7856871
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Abstract

Human aging is frequently accompanied by the acquisition of somatic mutations in the hematopoietic system that induce clonal hematopoiesis, leading to the development of a mutant clone of hematopoietic progenitors and leukocytes. This somatic-mutation-driven clonal hematopoiesis has been associated with an increased incidence of cardiovascular disease and type 2 diabetes, but whether this epidemiological association reflects a direct, causal contribution of mutant hematopoietic and immune cells to age-related metabolic abnormalities remains unexplored. Here, we show that inactivating mutations in the epigenetic regulator TET2, which lead to clonal hematopoiesis, aggravate age- and obesity-related insulin resistance in mice. This metabolic dysfunction is paralleled by increased expression of the pro-inflammatory cytokine IL-1β in white adipose tissue, and it is suppressed by pharmacological inhibition of NLRP3 inflammasome-mediated IL-1β production. These findings support a causal contribution of somatic TET2 mutations to insulin resistance and type 2 diabetes.

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  • Alternatives via adoptive transfer of unfractionated BM cells into nonirradiated mice are limited by a fixed availability of BM niche space and restricted starting clonal fractions.

    “Although alternatives have been established via adoptive transfer of unfractionated BM cells into nonirradiated mice, these models are limited by a fixed availability of BM niche space and, thus, restricted starting clonal fractions.40,41”

    From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [41]

    STAR★METHODS, Method Details (page unavailable), describes transfer of unfractionated bone marrow cells into nonirradiated mice. The Results on age-related insulin resistance (page unavailable) report a small initial donor-cell fraction, but neither passage attributes that fraction to fixed bone-marrow niche space or states that niche space restricts starting clonal fractions. (LLM, conf=0.84)

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Authors
Fuster, J. J., Zuriaga, M. A., Zorita, V., MacLauchlan, S., Polackal, M. N., Viana-Huete, V., Ferrer-Pérez, A., Matesanz, N., Herrero-Cervera, A., Sano, S., Cooper, M. A., González-Navarro, H., & Walsh, K.
Affiliations
  • Boston University (US)
  • Spanish National Centre for Cardiovascular Research (ES)
  • INCLIVA Health Research Institute (ES)
  • The University of Queensland (AU)
Corresponding author
  • Fuster, José J.
  • Walsh, Kenneth
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2020-10
Volume
33
Issue
4
Pages
108326
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2020.108326
PMC
PMC7856871
OpenAlex
W3094666465
Cited by
204
References
40
Citations by year
2026: 33 · 2025: 34 · 2024: 28 · 2023: 41 · 2022: 44 · 2021: 24
FWCI
19.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, other-oa)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health
  • Ministerio de Ciencia e Innovación
  • “la Caixa” Foundation
Topics
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
clonal hematopoiesis, TET2, loss-of-function mutations, somatic mutations, aging, obesity, insulin resistance, type 2 diabetes, IL-1β, NLRP3 inflammasome, white adipose tissue inflammation, hematopoietic progenitor cells, epigenetic regulation
MeSH terms
Clonal Hematopoiesis, Aging, Animals, DNA-Binding Proteins, Humans, Insulin Resistance, Obesity, Dioxygenases, Mice

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