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

• Published in: Cell reports (Cambridge) 2020-10, Vol.33 (4), p.108326-108326, Article 108326
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: adipose tissue; aging; CHIP; clonal hematopoiesis; diabetes; IL-1β; insulin resistance; obesity; somatic mutations; TET2
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •TET2-deficiency-driven clonal hematopoiesis aggravates insulin resistance in aged mice•TET2-deficiency-driven clonal hematopoiesis aggravates insulin resistance in obese mice•TET2-deficiency-driven clonal hematopoiesis increases IL-1β levels in adipose tissue•NLRP3 inhibition prevents the effects of TET2-deficient cells on insulin sensitivity Somatic-mutation-driven clonal hematopoiesis is emerging as a potent risk factor for a variety of age-related conditions. Fuster et al. show that clonal hematopoiesis driven by TET2 mutations aggravates insulin resistance in mice. These findings support a causal contribution of somatic TET2 mutations to metabolic syndrome and type 2 diabetes.