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

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-1? in white adipose tissue, and it is suppressed by pharmacological inhibition of NLRP3 inflammasome-mediated IL-1? production. These findings support a causal contribution of somatic TET2 mutations to insulin resistance and type 2 diabetes.

SUBMITTER: Fuster JJ 

PROVIDER: S-EPMC7856871 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature