Wt1 haploinsufficiency induces browning of epididymal fat and alleviates metabolic dysfunction in mice on high-fat diet,Diabetologia

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Wt1 haploinsufficiency induces browning of epididymal fat and alleviates metabolic dysfunction in mice on high-fat diet
Diabetologia ( IF 8.4 ) Pub Date : 2021-11-30 , DOI: 10.1007/s00125-021-05621-1
Karin M Kirschner ₁ , Anna Foryst-Ludwig _{2,

3} , Sabrina Gohlke ₄ , Chen Li ₂ , Roberto E Flores ₂ , Ulrich Kintscher _{2,

3} , Michael Schupp ₂ , Tim J Schulz _{4,

5,

6} , Holger Scholz ₁

Affiliation

Aims/hypothesis

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.

Methods

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.

Results

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.

Conclusion/interpretation

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.

Graphical abstract

中文翻译：

Wt1单倍体不足诱导附睾脂肪褐变并减轻高脂饮食小鼠的代谢功能障碍

目标/假设

尽管有类似的脂肪储存功能，但内脏（腹内）白色脂肪组织 (WAT) 是有害的，而皮下 WAT 被认为可以预防代谢疾病。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，我们研究了这样的假设：Wilms 肿瘤基因产物 (WT1) 在腹内 WAT 中表达，但在皮下 WAT 和 BAT 中不表达，抑制白色脂肪细胞中的产热程序。

方法

在产热和脂肪细胞选择性基因表达方面检查了杂合Wt1敲除小鼠及其野生型同窝仔。在正常食物和高脂肪饮食条件下评估这些小鼠的葡萄糖耐量和肝脏脂质积累。用表达Wt1的逆转录病毒转导从 BAT 基质血管部分分离的前脂肪细胞，诱导分化并分析产热和脂肪细胞选择性基因的表达。

结果

与野生型小鼠相比，杂合Wt1敲除小鼠的附睾 WAT 中产热基因Cpt1b和Tmem26的表达增强，并且Ucp1的转录水平平均高出十倍以上。Wt1杂合性降低了附睾 WAT 质量，改善了全身葡萄糖耐量并减轻了小鼠饮食诱导的肥胖后的严重肝脂肪变性。WT1 在缺乏内源性 WT1 的棕色前脂肪细胞中的逆转录病毒表达降低了Ucp1、Ppargc1a、Cidea、Prdm16和Cpt1b的 mRNA 水平在体外分化 60-90%。附睾前脂肪细胞中的 WT1 敲低显着降低了 Aldh1a1和Zfp423转录物，这是产热程序的两个关键抑制因子。相反，通过 WT1 在棕色前脂肪细胞中的逆转录病毒表达， Aldh1a1和Zfp423 mRNA 水平分别增加了大约 5 倍和 3 倍。