Twist-1是一种在棕色脂肪代谢中受PPARδ诱导的PGC-1α负反馈调节因子。
Twist-1 is a PPARdelta-inducible, negative-feedback regulator of PGC-1alpha in brown fat metabolism.
作者信息
Pan Dongning, Fujimoto Masaki, Lopes Andrea, Wang Yong-Xu
机构信息
Program in Gene Function and Expression and Program in Molecular Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
出版信息
Cell. 2009 Apr 3;137(1):73-86. doi: 10.1016/j.cell.2009.01.051.
Brown fat is specialized for energy expenditure, a process that is principally controlled by the transcriptional coactivator PGC-1alpha. Here, we describe a molecular network important for PGC-1alpha function and brown fat metabolism. We find that twist-1 is selectively expressed in adipose tissue, interacts with PGC-1alpha, and is recruited to the promoters of PGC-1alpha's target genes to suppress mitochondrial metabolism and uncoupling. In vivo, transgenic mice expressing twist-1 in the adipose tissue are prone to high-fat-diet-induced obesity, whereas twist-1 heterozygous knockout mice are obesity resistant. These phenotypes are attributed to their altered mitochondrial metabolism in the brown fat. Interestingly, the nuclear receptor PPARdelta not only mediates the actions of PGC-1alpha but also regulates twist-1 expression, suggesting a negative-feedback regulatory mechanism. These findings reveal an unexpected physiological role for twist-1 in the maintenance of energy homeostasis and have important implications for understanding metabolic control and metabolic diseases.
棕色脂肪专门用于能量消耗，这一过程主要由转录共激活因子PGC-1α控制。在此，我们描述了一个对PGC-1α功能和棕色脂肪代谢至关重要的分子网络。我们发现Twist-1在脂肪组织中选择性表达，与PGC-1α相互作用，并被招募到PGC-1α靶基因的启动子上以抑制线粒体代谢和解偶联。在体内，在脂肪组织中表达Twist-1的转基因小鼠易患高脂饮食诱导的肥胖症，而Twist-1杂合敲除小鼠具有抗肥胖能力。这些表型归因于它们棕色脂肪中线粒体代谢的改变。有趣的是，核受体PPARδ不仅介导PGC-1α的作用，还调节Twist-1的表达，提示存在负反馈调节机制。这些发现揭示了Twist-1在维持能量稳态中的意外生理作用，对理解代谢控制和代谢疾病具有重要意义。
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