Regulation of SNS-dependent Remodeling of Adipose Tissue by a Novel Form of PGC-1

描述（由申请人提供）：SNS通过调节影响细胞蛋白质组重塑的转录程序整合代谢组织的功能。有证据支持PGC1是连接p-肾上腺素能受体与转录程序的关键转录共激活因子，这些转录程序具有通过协调诱导核编码线粒体基因来增加氧化能力的共同主题。我们发现了PGC1的一个新的剪接变体，它产生一个截断的蛋白，代表n端的前267个AAs和剪接插入的另外3个AAs。N - 270aa蛋白（NT-PGC1）的表达在调控全长蛋白的生理信号的背景下受到动态调控。更重要的是，我们通过一系列全面的初步实验表明，其独特的结构域结构具有显著的体外和体内特性，可以增强sns依赖性脂肪组织重塑。总的来说，这些数据一致地与NT-PGC1是将SNS输入转化为转录反应的信号系统中一个重要的、以前未被识别的组成部分的概念一致。尽管目前的研究主要集中在脂肪组织，但更好地了解NT-PGC1在脂肪组织中的作用对其他组织如肝脏和肌肉也有广泛的意义，其中PGC1功能的调节也至关重要。我们已经创建了以脂肪组织特异性和诱导方式表达NT-PGC1的细胞系和转基因小鼠。在补充研究中，棕色脂肪细胞将从PGC1缺失小鼠中永生，然后通过稳定转化重新引入NT-PGC1或PGC1，以评估每种剪接变体的独特功能。我们的目标是评估这种新蛋白在体内和体外的作用，以及它如何调节pgc1依赖过程和调节交感神经输入到脂肪和其他代谢活跃组织的翻译。

DESCRIPTION (provided by applicant): The SNS integrates the function of metabolic tissues through regulation of transcriptional programs that effect remodeling of the cellular proteome. Evidence has emerged to support the view that PGC1 is the critical transcriptional co-activator linking p-adrenergic receptors to transcriptional programs which have the common theme of increasing oxidative capacity through coordinated induction of nuclear-encoded mitochondrial genes. We have discovered a novel splice variant of PGC1 which produces a truncated protein representing the first 267 AAs of the N-terminus and an additional 3 AAs from the splicing insert. Expression of the N trucated 270 AA protein (NT-PGC1) is dynamically regulated in the context of physiological signals which regulate full length protein. More importantly, we have shown through a comprehensive series of preliminary experiments that its unique domain structure conveys significant in vitro and in vivo properties which enhance SNS-dependent adipose tissue remodeling. Collectively, these data are uniformly consistent with the concept that NT-PGC1 is an important, previously unrecognized component of the signaling system which translates SNS input into transcriptional responses. Although the present proposal is focused on adipose tissue, a better understanding of how NT-PGC1 functions here has broad implications with respect to other tissues like liver and muscle where regulation of PGC1 function is also critical. We have created cell lines and transgenic mice which express NT-PGC1 in an adipose tissue-specific and inducible manner. In complementary studies, brown adipocytes will be immortalized from PGC1 null mice, followed by reintroduction of NT-PGC1 or PGC1 by stable transformation to assess the unique function of each splice variant. Our goal is to assess the in vivo and in vitro role of this novel protein with respect to how it regulates PGC1-dependent processe and regulates the translation of sympathetic input into adipose and other metabolically active tissues.