Dact1, a nutritionally regulated preadipocyte gene, controls adipogenesis by coordinating the Wnt/beta-catenin signaling network.
Dact1, a nutritionally regulated preadipocyte gene, controls adipogenesis by coordinating the Wnt/beta-catenin signaling network.
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DOI：
10.2337/db08-1180
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发表时间：
2009-03
期刊：
影响因子：
7.7
通讯作者：
Sethi, Jaswinder K.
中科院分区：
文献类型：
--
作者：
Lagathu, Claire;Christodoulides, Constantinos;Virtue, Sam;Cawthorn, William P.;Franzin, Chiara;Kimber, Wendy A.;Nora, Edoardo Dalla;Campbell, Mark;Medina-Gomez, Gema;Cheyette, Benjamin N. R.;Vidal-Puig, Antonio J.;Sethi, Jaswinder K.
Wnt信号转导抑制脂肪形成，但其调节，生理相关性和分子效应器知之甚少。在这里，我们将Wnt调节剂Dapper 1/Frodo 1（Dact 1）确定为一种新的前脂肪细胞基因，参与调节小鼠和人类脂肪形成。研究设计和方法-在三种体外脂肪形成模型中研究了Dact 1表达的变化。体外获得和丧失功能的研究被用来研究Dact 1在脂肪形成过程中的作用机制。在营养状态改变、体内脂肪形成的药理学刺激以及饮食和遗传性肥胖发展过程中的小鼠模型中研究了Dact 1和Wnt/β-连环蛋白信号传导的体内调节。Dact 1是一个前脂肪细胞基因，在脂肪形成过程中减少。然而，Dact 1敲低通过激活Wnt/β-连环蛋白信号传导途径损害脂肪形成，并且这通过用分泌的Wnt拮抗剂分泌的卷曲相关蛋白1（Sfrp 1）处理而逆转。相反，组成性Dact 1过表达促进脂肪形成，并通过增加内源性Sfrps的表达和减少Wnt的表达来赋予对Wnt配体诱导的抗脂肪形成的抗性。在体内，在白色脂肪组织中，Dact 1和Wnt/β-连环蛋白信号传导也表现出协调的表达谱，以响应改变的营养状态，响应体内脂肪形成的药理学刺激，以及在饮食和遗传性肥胖的发展过程中。结论-Dact 1通过对基因表达的协同作用调节脂肪形成，选择性地改变Wnt/β-catenin信号通路的细胞内和旁分泌/自分泌组分。这些对控制脂肪组织可塑性的分子机制的新见解提供了具有治疗疾病（如肥胖和相关代谢紊乱）潜力的功能网络。
OBJECTIVE—Wnt signaling inhibits adipogenesis, but its regulation, physiological relevance, and molecular effectors are poorly understood. Here, we identify the Wnt modulator Dapper1/Frodo1 (Dact1) as a new preadipocyte gene involved in the regulation of murine and human adipogenesis. RESEARCH DESIGN AND METHODS—Changes in Dact1 expression were investigated in three in vitro models of adipogenesis. In vitro gain- and loss-of-function studies were used to investigate the mechanism of Dact1 action during adipogenesis. The in vivo regulation of Dact1 and Wnt/β-catenin signaling were investigated in murine models of altered nutritional status, of pharmacological stimulation of in vivo adipogenesis, and during the development of dietary and genetic obesity. RESULTS—Dact1 is a preadipocyte gene that decreases during adipogenesis. However, Dact1 knockdown impairs adipogenesis through activation of the Wnt/β-catenin signaling pathway, and this is reversed by treatment with the secreted Wnt antagonist, secreted Frizzled-related protein 1 (Sfrp1). In contrast, constitutive Dact1 overexpression promotes adipogenesis and confers resistance to Wnt ligand-induced antiadipogenesis through increased expression of endogenous Sfrps and reduced expression of Wnts. In vivo, in white adipose tissue, Dact1 and Wnt/β-catenin signaling also exhibit coordinated expression profiles in response to altered nutritional status, in response to pharmacological stimulation of in vivo adipogenesis, and during the development of dietary and genetic obesity. CONCLUSIONS—Dact1 regulates adipogenesis through coordinated effects on gene expression that selectively alter intracellular and paracrine/autocrine components of the Wnt/β-catenin signaling pathway. These novel insights into the molecular mechanisms controlling adipose tissue plasticity provide a functional network with therapeutic potential against diseases, such as obesity and associated metabolic disorders.
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DOI：
10.1210/me.2005-0536
发表时间：
2006-08
期刊：
Molecular endocrinology (Baltimore, Md.)
影响因子：
--
作者：
Nawaratne R;Gray A;Jørgensen CH;Downes CP;Siddle K;Sethi JK
通讯作者：
Sethi JK
影响因子：
4.6
作者：
Hikasa, H;Sokol, SY
通讯作者：
Sokol, SY
影响因子：
7.7
作者：
Gray, Sarah L.;Nora, Edoardo Dalla;Vidal-Puig, Antonio
通讯作者：
Vidal-Puig, Antonio
影响因子：
11.8
作者：
Cheyette, BNR;Waxman, JS;Moon, RT
通讯作者：
Moon, RT
影响因子：
16
作者：
Wong, HC;Bourdelas, A;Zheng, J
通讯作者：
Zheng, J