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TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity

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...

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Autores principales: Fuster, José J., Zuriaga, María A., Zorita, Virginia, MacLauchlan, Susan, Polackal, Maya N., Viana-Huete, Vanesa, Ferrer-Pérez, Alba, Matesanz, Nuria, Herrero-Cervera, Andrea, Sano, Soichi, Cooper, Matthew A., González-Navarro, Herminia, Walsh, Kenneth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856871/
https://www.ncbi.nlm.nih.gov/pubmed/33113366
http://dx.doi.org/10.1016/j.celrep.2020.108326
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author Fuster, José J.
Zuriaga, María A.
Zorita, Virginia
MacLauchlan, Susan
Polackal, Maya N.
Viana-Huete, Vanesa
Ferrer-Pérez, Alba
Matesanz, Nuria
Herrero-Cervera, Andrea
Sano, Soichi
Cooper, Matthew A.
González-Navarro, Herminia
Walsh, Kenneth
author_facet Fuster, José J.
Zuriaga, María A.
Zorita, Virginia
MacLauchlan, Susan
Polackal, Maya N.
Viana-Huete, Vanesa
Ferrer-Pérez, Alba
Matesanz, Nuria
Herrero-Cervera, Andrea
Sano, Soichi
Cooper, Matthew A.
González-Navarro, Herminia
Walsh, Kenneth
author_sort Fuster, José J.
collection PubMed
description 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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spelling pubmed-78568712021-02-03 TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity Fuster, José J. Zuriaga, María A. Zorita, Virginia MacLauchlan, Susan Polackal, Maya N. Viana-Huete, Vanesa Ferrer-Pérez, Alba Matesanz, Nuria Herrero-Cervera, Andrea Sano, Soichi Cooper, Matthew A. González-Navarro, Herminia Walsh, Kenneth Cell Rep Article 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. 2020-10-27 /pmc/articles/PMC7856871/ /pubmed/33113366 http://dx.doi.org/10.1016/j.celrep.2020.108326 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Fuster, José J.
Zuriaga, María A.
Zorita, Virginia
MacLauchlan, Susan
Polackal, Maya N.
Viana-Huete, Vanesa
Ferrer-Pérez, Alba
Matesanz, Nuria
Herrero-Cervera, Andrea
Sano, Soichi
Cooper, Matthew A.
González-Navarro, Herminia
Walsh, Kenneth
TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity
title TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity
title_full TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity
title_fullStr TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity
title_full_unstemmed TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity
title_short TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity
title_sort tet2-loss-of-function-driven clonal hematopoiesis exacerbates experimental insulin resistance in aging and obesity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856871/
https://www.ncbi.nlm.nih.gov/pubmed/33113366
http://dx.doi.org/10.1016/j.celrep.2020.108326
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