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

Cell Rep. 2020 Oct 27;33(4):108326. doi: 10.1016/j.celrep.2020.108326.


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.

Keywords: CHIP; IL-1β; TET2; adipose tissue; aging; clonal hematopoiesis; diabetes; insulin resistance; obesity; somatic mutations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Clonal Hematopoiesis / genetics*
  • DNA-Binding Proteins / metabolism*
  • Dioxygenases / metabolism*
  • Humans
  • Insulin Resistance / genetics*
  • Mice
  • Obesity / genetics*


  • DNA-Binding Proteins
  • Dioxygenases
  • TET2 protein, human