Wt1 haploinsufficiency induces browning of epididymal fat and alleviates metabolic dysfunction in mice on high-fat diet.
Wt1 haploinsufficiency induces browning of epididymal fat and alleviates metabolic dysfunction in mice on high-fat diet.
复制标题
DOI：
10.1007/s00125-021-05621-1
复制
发表时间：
2022-03
期刊：
影响因子：
8.2
通讯作者：
Scholz H
中科院分区：
文献类型：
--
作者：
Kirschner KM;Foryst-Ludwig A;Gohlke S;Li C;Flores RE;Kintscher U;Schupp M;Schulz TJ;Scholz H
尽管有类似的脂肪储存功能，内脏（腹内）白色脂肪组织（WAT）是有害的，而皮下的WAT被认为可以防止代谢疾病。最近的研究结果表明，在棕色脂肪组织（BAT）中表达的产热基因可以主要在皮下WAT中被诱导。在这里，我们研究了Wilms肿瘤基因产物（WT1）抑制白色脂肪细胞产热程序的假设，WT1在腹腔WAT中表达，而在皮下WAT和BAT中不表达。对Wt1基因敲除的杂合小鼠及其野生型仔鼠进行了产热性和脂肪细胞选择性基因表达的检测。在正常食物和高脂肪饮食条件下，对这些小鼠的葡萄糖耐量和肝脏脂质积累进行了评估。用表达wt1的逆转录病毒转导从BAT间质血管部分分离的前脂肪细胞，诱导分化并分析产热基因和脂肪细胞选择基因的表达。产热基因Cpt1b和Tmem26的表达增强，与野生型小鼠相比，杂合Wt1敲除小鼠附睾WAT中Ucp1的转录水平平均高出10倍以上。Wt1杂合性降低了附睾WAT质量，提高了全身葡萄糖耐量，减轻了小鼠饮食性肥胖后严重的肝脏脂肪变性。在缺乏内源性WT1的褐色前脂肪细胞中，逆转录病毒表达WT1可使体外分化后的Ucp1、Ppargc1a、Cidea、Prdm16和Cpt1b mRNA水平降低60-90%。在附睾前脂肪细胞中，WT1的下调显著降低了Aldh1a1和Zfp423转录本，这是产热程序的两个关键抑制因子。相反，在棕色前脂肪细胞中，通过逆转录病毒表达WT1， Aldh1a1和Zfp423 mRNA水平分别增加了约5倍和3倍。WT1通过抑制产热基因在附睾WAT中起白色脂肪细胞决定因子的作用。降低Wt1在这个和其他腹内脂肪库中的表达可能是代谢性疾病的一种新的治疗策略。本文的在线版本（10.1007/s00125-021-05621-1）包含同行评审但未经编辑的补充材料。
Despite a similar fat storing function, visceral (intra-abdominal) white adipose tissue (WAT) is detrimental, whereas subcutaneous WAT is considered to protect against metabolic disease. Recent findings indicate that thermogenic genes, expressed in brown adipose tissue (BAT), can be induced primarily in subcutaneous WAT. Here, we investigate the hypothesis that the Wilms tumour gene product (WT1), which is expressed in intra-abdominal WAT but not in subcutaneous WAT and BAT, suppresses a thermogenic program in white fat cells. Heterozygous Wt1 knockout mice and their wild-type littermates were examined in terms of thermogenic and adipocyte-selective gene expression. Glucose tolerance and hepatic lipid accumulation in these mice were assessed under normal chow and high-fat diet conditions. Pre-adipocytes isolated from the stromal vascular fraction of BAT were transduced with Wt1-expressing retrovirus, induced to differentiate and analysed for the expression of thermogenic and adipocyte-selective genes. Expression of the thermogenic genes Cpt1b and Tmem26 was enhanced and transcript levels of Ucp1 were on average more than tenfold higher in epididymal WAT of heterozygous Wt1 knockout mice compared with wild-type mice. Wt1 heterozygosity reduced epididymal WAT mass, improved whole-body glucose tolerance and alleviated severe hepatic steatosis upon diet-induced obesity in mice. Retroviral expression of WT1 in brown pre-adipocytes, which lack endogenous WT1, reduced mRNA levels of Ucp1, Ppargc1a, Cidea, Prdm16 and Cpt1b upon in vitro differentiation by 60–90%. WT1 knockdown in epididymal pre-adipocytes significantly lowered Aldh1a1 and Zfp423 transcripts, two key suppressors of the thermogenic program. Conversely, Aldh1a1 and Zfp423 mRNA levels were increased approximately five- and threefold, respectively, by retroviral expression of WT1 in brown pre-adipocytes. WT1 functions as a white adipocyte determination factor in epididymal WAT by suppressing thermogenic genes. Reducing Wt1 expression in this and other intra-abdominal fat depots may represent a novel treatment strategy in metabolic disease. The online version of this article (10.1007/s00125-021-05621-1) contains peer-reviewed but unedited supplementary material.
登录
查看更多内容
影响因子：
29
作者：
Kajimura S;Spiegelman BM;Seale P
通讯作者：
Seale P
DOI：
10.1126/science.1190816
发表时间：
2010-05-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ishibashi J;Seale P
通讯作者：
Seale P
视网膜甲醛脱氢酶1调节白色脂肪组织中的热程序。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
64.5
作者：
KREIDBERG, JA;SARIOLA, H;JAENISCH, R
通讯作者：
JAENISCH, R
影响因子：
4.8
作者：
Kirschner, Karin M.;Sciesielski, Lina K.;Scholz, Holger
通讯作者：
Scholz, Holger