Fetal development of subcutaneous white adipose tissue is dependent on Zfp423.
Fetal development of subcutaneous white adipose tissue is dependent on Zfp423.
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DOI：
10.1016/j.molmet.2016.11.009
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发表时间：
2017-01
影响因子：
8.1
通讯作者：
Gupta RK
中科院分区：
文献类型：
--
作者：
Shao M;Hepler C;Vishvanath L;MacPherson KA;Busbuso NC;Gupta RK
Zfp 423是一种在体内前脂肪细胞和成熟脂肪细胞中表达的多锌指转录因子。我们最近的工作揭示了Zfp 423通过抑制米色细胞产热基因程序在维持成年小鼠白色脂肪细胞命运中的关键作用;成年小鼠成熟脂肪细胞中Zfp 423的缺失导致白色至米色表型转换。然而，Zfp 423在体内早期脂肪发育的胎儿阶段的确切需求尚未阐明。在这里，我们利用两种模型，赋予胎儿脂肪发育过程中脂肪特异性Zfp 423失活（脂连蛋白-Cre; Zfp 423 loxP/loxP和脂连蛋白-rtTA; TRE-Cre; Zfp 423 loxP/loxP）。我们评估了胎儿脂肪Zfp 423缺失对脂肪组织初始形成的影响，并评估了用高脂饮食喂养挑战这些动物的代谢后果。在胎儿脂肪发育期间缺失Zfp 423导致与在成年小鼠的脂肪细胞中缺失Zfp 423时观察到的表型不同的表型。在胎儿脂肪发育过程中Zfp 423的失活导致分化停滞，特别是腹股沟白色脂肪细胞，而不是当Zfp 423在成年小鼠中失活时发生的白色至米色表型转换。这可能是通过观察到脂联素驱动的Cre表达在胎儿皮下脂肪发育期间的脂肪细胞生命周期的早期阶段比在成年小鼠中活跃来解释的。在高脂肪饮食喂养后，肥胖脂肪Zfp 423缺陷动物经历病理性脂肪组织扩张，与异位脂质沉积和全身胰岛素抵抗相关。我们的研究结果表明，Zfp 423是必不可少的终端分化的皮下白色脂肪细胞在胎儿脂肪组织发育。此外，我们的数据强调了肥胖症患者病理性皮下脂肪组织重塑对内脏脂肪功能和全身营养平衡的显著不良影响。重要的是，这些数据揭示了当脂联素驱动的转基因在胎儿与成人脂肪组织中被激活时可能发生的不同表型。Zfp 423的胎儿脂肪缺失破坏了白色脂肪细胞的终末分化。Zfp 423缺陷型小鼠的腹股沟WAT在肥胖中经历病理性扩张。皮下脂肪的病理性扩张触发全身性胰岛素抵抗。
Zfp423 is a multi zinc-finger transcription factor expressed in preadipocytes and mature adipocytes in vivo. Our recent work has revealed a critical role for Zfp423 in maintaining the fate of white adipocytes in adult mice through suppression of the beige cell thermogenic gene program; loss of Zfp423 in mature adipocytes of adult mice results in a white-to-beige phenotypic switch. However, the exact requirements of Zfp423 in the fetal stages of early adipose development in vivo have not been clarified. Here, we utilize two models that confer adipose-specific Zfp423 inactivation during fetal adipose development (Adiponectin-Cre; Zfp423loxP/loxP and Adiponectin-rtTA; TRE-Cre; Zfp423loxP/loxP). We assess the impact of fetal adipose Zfp423 deletion on the initial formation of adipose tissue and evaluate the metabolic consequences of challenging these animals with high-fat diet feeding. Deletion of Zfp423 during fetal adipose development results in a different phenotype than is observed when deleting Zfp423 in adipocytes of adult mice. Inactivation of Zfp423 during fetal adipose development results in arrested differentiation, specifically of inguinal white adipocytes, rather than a white-to-beige phenotypic switch that occurs when Zfp423 is inactivated in adult mice. This is likely explained by the observation that adiponectin driven Cre expression is active at an earlier stage of the adipocyte life cycle during fetal subcutaneous adipose development than in adult mice. Upon high-fat diet feeding, obese adipose Zfp423-deficient animals undergo a pathological adipose tissue expansion, associated with ectopic lipid deposition and systemic insulin resistance. Our results reveal that Zfp423 is essential for the terminal differentiation of subcutaneous white adipocytes during fetal adipose tissue development. Moreover, our data highlight the striking adverse effects of pathological subcutaneous adipose tissue remodeling on visceral adipose function and systemic nutrient homeostasis in obesity. Importantly, these data reveal the distinct phenotypes that can occur when adiponectin driven transgenes are activated in fetal vs. adult adipose tissue. Fetal adipose deletion of Zfp423 disrupts terminal differentiation of white adipocytes. Inguinal WAT of Zfp423-deficient mice undergoes a pathological expansion in obesity. Pathological expansion of subcutaneous adipose triggers systemic insulin resistance.
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影响因子：
37.8
作者：
Gealekman O;Guseva N;Hartigan C;Apotheker S;Gorgoglione M;Gurav K;Tran KV;Straubhaar J;Nicoloro S;Czech MP;Thompson M;Perugini RA;Corvera S
通讯作者：
Corvera S
影响因子：
7.7
作者：
Gustafson B;Hammarstedt A;Hedjazifar S;Smith U
通讯作者：
Smith U
DOI：
10.1073/pnas.0609184103
发表时间：
2006-12-19
影响因子：
11.1
作者：
Alcaraz, Wendy A.;Gold, David A.;Hamilton, Bruce A.
通讯作者：
Hamilton, Bruce A.
影响因子：
64.5
作者：
Kissig M;Shapira SN;Seale P
通讯作者：
Seale P
影响因子：
4.6
作者：
Hong, Ki Yong;Bae, Hosung;Koh, Gou Young
通讯作者：
Koh, Gou Young