期刊
CELL REPORTS
卷 33, 期 4, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.108326
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资金
- European Foundation for the Study of Diabetes
- Spanish Ministerio de Ciencia e Innovacion [RYC-2016-20026, RTI2018-093554-A-I00]
- National Institutes of Health [HL152174, HL139819, HL138014, HL141256, HL142650]
- la Caixa Foundation [100010434, HR17-00267]
- 2019 Leonardo Grant for Researchers and Cultural Creators from the BBVA Foundation, Madrid, Spain
- Instituto de Salud Carlos III (ISCIII)
- Ministerio de Ciencia e Innovacion
- Pro CNIC Foundation
- Lilly European Diabetes Research Programme
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-1 beta in white adipose tissue, and it is suppressed by pharmacological inhibition of NLRP3 inflammasome-mediated IL-1 beta production. These findings support a causal contribution of somatic TET2 mutations to insulin resistance and type 2 diabetes.
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