Objective

T-box 1 (TBX1) has been identified as a genetic marker of beige adipose tissue. TBX1 is a mesodermal development transcription factor essential for tissue patterning and cell fate determination. However, whether it plays a role in the process of adipose beiging or how it functions in adipose tissue has not been reported. Here, we examined the function of TBX1 in adipose tissue as well as adipose-derived stem cells from mice and humans.

Methods

Adipose-specific TBX1 transgenic (TBX1 AdipoTG) and adipose-specific TBX1 knockout (TBX1 AdipoKO) mice were generated to explore the function of TBX1 in the process of adipose beiging, metabolism and energy homeostasis in vivo. In vitro, we utilized a siRNA mediated approach to determine the function of TBX1 during adipogenesis in mouse and human stem cells.

Results

Adipose-specific overexpression of TBX1 was not sufficient to fully induce beiging and prevent diet-induced obesity. However, adipose TBX1 expression was necessary to defend body temperature during cold through regulation of UCP1 and for maintaining β3-adrenergic sensitivity and glucose homeostasis in vivo. Loss of adipose TBX1 expression enhanced basal lipolysis and reduced the size of subcutaneous iWAT adipocytes. Reduction of TBX1 expression via siRNA significantly impaired adipogenesis of mouse stromal vascular cells but significantly enhanced adipogenesis in human adipose derived stem cells.

Conclusions

Adipose expression of TBX1 is necessary, but not sufficient, to defend body temperature during cold via proper UCP1 expression. Adipose TBX1 expression was also required for proper insulin signaling in subcutaneous adipose as well as for maintaining β-adrenergic sensitivity, but overexpression of TBX1 was not sufficient to induce adipocyte beiging or to prevent diet-induced obesity. TBX1 expression is enriched in adipose stem cells in which it has contrasting effects on adipogenesis in mouse versus human cells. Collectively, these data demonstrate the importance of adipose TBX1 in the regulation of beige adipocyte function, energy homeostasis, and adipocyte development.

中文翻译：

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脂肪TBX1调节皮下脂肪组织中的β-肾上腺素敏感性和体内生热能力。

目的

T-box 1（TBX1）已被识别为米色脂肪组织的遗传标记。TBX1是中胚层发育转录因子，对于组织模式和细胞命运测定至关重要。然而，它在脂肪形成过程中是否起作用或在脂肪组织中如何发挥作用尚无报道。在这里，我们检查了TBX1在小鼠和人类的脂肪组织以及脂肪干细胞中的功能。

方法

产生了脂肪特异性TBX1转基因（TBX1 AdipoTG）和脂肪特异性TBX1敲除（TBX1 AdipoKO）小鼠，以探索TBX1在体内脂肪形成，代谢和能量稳态过程中的功能。在体外，我们利用siRNA介导的方法来确定TBX1在小鼠和人类干细胞成脂过程中的功能。

结果

特定于脂肪的TBX1过表达不足以完全诱导肥胖和预防饮食引起的肥胖。然而，脂肪TBX1的表达对于通过调节UCP1来维持寒冷时的体温以及维持体内的β3肾上腺素敏感性和葡萄糖稳态是必需的。脂肪TBX1表达的丧失增强了基础脂解作用，并减少了皮下iWAT脂肪细胞的大小。通过siRNA减少TBX1表达可显着损害小鼠基质血管细胞的脂肪生成，但可显着增强人脂肪干细胞的脂肪生成。

结论

TBX1的脂肪表达是必需的，但不足以通过适当的UCP1表达来捍卫寒冷时的体温。皮下脂肪中适当的胰岛素信号传导以及维持β-肾上腺素敏感性也需要脂肪TBX1的表达，但是TBX1的过表达不足以诱导脂肪细胞增高或防止饮食诱导的肥胖。TBX1表达富集在脂肪干细胞中，在脂肪干细胞中，它对小鼠和人细胞的脂肪生成具有相反的作用。总的来说，这些数据表明脂肪TBX1在调节米色脂肪细胞功能，能量稳态和脂肪细胞发育中的重要性。