脂肪组织中的TBX1调节皮下脂肪组织中的β-肾上腺素能敏感性和体内产热能力。

Adipose TBX1 regulates β-adrenergic sensitivity in subcutaneous adipose tissue and thermogenic capacity in vivo.

作者信息

Markan Kathleen R, Boland Lauren K, King-McAlpin Abdul Qaadir, Claflin Kristin E, Leaman Michael P, Kemerling Morgan K, Stonewall Madison M, Amendt Brad A, Ankrum James A, Potthoff Matthew J

机构信息

Department of Neuroscience and Pharmacology, Iowa City, IA, 52242, USA; Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, 52242, USA.

Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, 52242, USA; Roy J. Carver Department of Biomedical Engineering, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.

出版信息

Mol Metab. 2020 Jun;36:100965. doi: 10.1016/j.molmet.2020.02.008. Epub 2020 Feb 18.

DOI:10.1016/j.molmet.2020.02.008

PMID:32240964

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7115112/

Abstract

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.

摘要

目的

T盒1（TBX1）已被确定为米色脂肪组织的遗传标志物。TBX1是一种中胚层发育转录因子，对组织模式形成和细胞命运决定至关重要。然而，它是否在脂肪米色化过程中发挥作用，以及如何在脂肪组织中发挥功能尚未见报道。在此，我们研究了TBX1在小鼠和人类脂肪组织以及脂肪来源干细胞中的功能。

方法

构建脂肪特异性TBX1转基因（TBX1 AdipoTG）和脂肪特异性TBX1敲除（TBX1 AdipoKO）小鼠，以探究TBX1在体内脂肪米色化、代谢和能量稳态过程中的功能。在体外，我们采用小干扰RNA介导的方法来确定TBX1在小鼠和人类干细胞脂肪生成过程中的功能。

结果

脂肪特异性过表达TBX1不足以完全诱导米色化和预防饮食诱导的肥胖。然而，脂肪TBX1的表达对于在寒冷状态下通过调节解偶联蛋白1（UCP1）来维持体温以及在体内维持β3-肾上腺素能敏感性和葡萄糖稳态是必要的。脂肪TBX1表达缺失增强了基础脂肪分解，并减小了皮下腹股沟白色脂肪组织（iWAT）脂肪细胞的大小。通过小干扰RNA降低TBX1表达显著损害了小鼠基质血管细胞的脂肪生成，但显著增强了人类脂肪来源干细胞的脂肪生成。

结论

脂肪中TBX1的表达对于在寒冷状态下通过适当表达UCP1来维持体温是必要的，但并不充分。皮下脂肪中适当的胰岛素信号传导以及维持β-肾上腺素能敏感性也需要脂肪TBX1的表达，但TBX1过表达不足以诱导脂肪细胞米色化或预防饮食诱导的肥胖。TBX1在脂肪干细胞中表达丰富，它对小鼠和人类细胞的脂肪生成具有相反的作用。总体而言，这些数据证明了脂肪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。