Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis.
Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis.
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DOI：
10.7554/elife.72359
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发表时间：
2022-05-30
期刊：
影响因子：
7.7
通讯作者：
Goodell, Margaret A.
中科院分区：
文献类型：
--
作者：
Tovy, Ayala;Reyes, Jaime M.;Zhang, Linda;Huang, Yung-Hsin;Rosas, Carina;Daquinag, Alexes C.;Guzman, Anna;Ramabadran, Raghav;Chen, Chun-Wei;Gu, Tianpeng;Gupta, Sinjini;Ortinau, Laura;Park, Dongsu;Cox, Aaron R.;Rau, Rachel E.;Hartig, Sean M.;Kolonin, Mikhail G.;Goodell, Margaret A.
DNA甲基转移酶3a （DNMT3A）是胚胎干细胞和造血干细胞分化的重要促进因子。DNMT3A杂合子种系突变可导致塔顿-布朗-拉赫曼综合征（TBRS），其特征是肥胖和身高过高。虽然已知DNMT3A通过下丘脑影响进食行为，但在这里，我们利用杂合敲除小鼠研究了其在脂肪细胞祖细胞中的作用，这些小鼠重现了主要的TBRS表型。这些小鼠由于脂肪细胞增大和组织扩张而变得病态肥胖。这些小鼠的脂肪组织在脂肪前细胞成熟和炎症基因网络（包括白细胞介素-6信号）的过早激活方面表现出缺陷。缺乏DNMT3A的脂肪细胞祖细胞系表现出异常分化。此外，在脂肪细胞祖细胞中特异性消融Dnmt3a的小鼠显示脂肪库增加，祖细胞数量增加，部分再现了TBRS肥胖表型。DNMT3A缺失导致组成性DNA低甲基化，使得年轻脂肪细胞祖细胞的DNA甲基化景观与老年野生型小鼠相似。总之，我们的研究结果表明，DNMT3A协调了维持正常体重和预防炎症性肥胖所需的能量储存的中央和局部控制。
DNA Methyltransferase 3 A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A exhibited aberrant differentiation. Furthermore, mice in which Dnmt3a was specifically ablated in adipocyte progenitors showed enlarged fat depots and increased progenitor numbers, partly recapitulating the TBRS obesity phenotypes. Loss of DNMT3A led to constitutive DNA hypomethylation, such that the DNA methylation landscape of young adipocyte progenitors resemble that of older wild-type mice. Together, our results demonstrate that DNMT3A coordinates both the central and local control of energy storage required to maintain normal weight and prevent inflammatory obesity.