Fuster, Jose J.Zuriaga, María AZorita, VirginiaMacLauchlan, SusanPolackal, Maya NViana-Huete, VanesaFerrer-Pérez, AlbaMatesanz, NuriaHerrero-Cervera, AndreaSano, SoichiCooper, Matthew AGonzález-Navarro, HerminiaWalsh, Kenneth2020-11-042020-11-042020-10-27Cell Rep. 2020; 33(4):1083262211-1247http://hdl.handle.net/20.500.12105/11280Human 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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 Internacional3311336633410832610.1016/j.celrep.2020.108326Cell reportsopen access