TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity.
TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity.
复制标题
TET2功能驱动的克隆造血作用加剧了衰老和肥胖症中的实验性胰岛素抵抗。
DOI：
10.1016/j.celrep.2020.108326
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发表时间：
2020-10-27
期刊：
影响因子：
8.8
通讯作者：
Walsh K
中科院分区：
文献类型：
--
作者：
Fuster JJ;Zuriaga MA;Zorita V;MacLauchlan S;Polackal MN;Viana-Huete V;Ferrer-Pérez A;Matesanz N;Herrero-Cervera A;Sano S;Cooper MA;González-Navarro H;Walsh K
人类衰老通常伴随着造血系统中体细胞突变的获得，从而诱导克隆造血，导致造血祖细胞和白细胞的突变克隆的发展。这种体细胞突变驱动的克隆造血与心血管疾病和2型糖尿病发病率的增加有关，但这种流行病学关联是否反映了突变的造血细胞和免疫细胞对年龄相关代谢异常的直接因果贡献仍未研究。在这里，我们发现导致克隆造血的表观遗传调控因子TET2失活突变，加剧了小鼠年龄和肥胖相关的胰岛素抵抗。这种代谢功能障碍与白色脂肪组织中促炎细胞因子IL-1β的表达增加有关，并通过抑制NLRP3炎症小体介导的IL-1β的产生而受到抑制。这些发现支持了体细胞TET2突变对胰岛素抵抗和2型糖尿病的因果贡献。体细胞突变驱动的克隆造血正在成为各种年龄相关疾病的潜在危险因素。Fuster等人的研究表明，TET2突变驱动的克隆造血会加重小鼠的胰岛素抵抗。这些发现支持了体细胞TET2突变对代谢综合征和2型糖尿病的因果贡献。
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. 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.
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DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
30.8
作者：
Bonnefond, Amelie;Skrobek, Boris;Froguel, Philippe
通讯作者：
Froguel, Philippe
影响因子：
11.4
作者：
Arends, Christopher Maximilian;Galan-Sousa, Joel;Damm, Frederik
通讯作者：
Damm, Frederik
影响因子：
20.3
作者：
Buscarlet, Manuel;Provost, Sylvie;Busque, Lambert
通讯作者：
Busque, Lambert
影响因子：
24
作者：
Sano S;Oshima K;Wang Y;MacLauchlan S;Katanasaka Y;Sano M;Zuriaga MA;Yoshiyama M;Goukassian D;Cooper MA;Fuster JJ;Walsh K
通讯作者：
Walsh K