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来整合代谢组织的功能。已有证据支持这样的观点，即PGC1是关键的转录辅助激活因子，将p-肾上腺素能受体与转录程序联系起来，转录程序的共同主题是通过协调诱导核编码的线粒体基因来增强氧化能力。我们发现了一种新的PGC1剪接变异体，它产生一个截断的蛋白，代表N-末端的前267个氨基酸和剪接插入的另外3个氨基酸。N结构的270氨基酸蛋白(NT-PGC1)的表达是在调节全长蛋白质的生理信号的背景下动态调节的。更重要的是，我们已经通过一系列全面的初步实验表明，其独特的结构域结构在体外和体内都传达了显著的特性，这些特性促进了SNS依赖的脂肪组织重塑。总的来说，这些数据与NT-PGC1是信号系统中一个重要的、以前未被识别的组件的概念一致，该信号系统将SNS输入转换为转录反应。虽然目前的建议集中在脂肪组织上，但更好地了解NT-PGC1在这里的功能对于其他组织，如肝脏和肌肉，也具有广泛的意义，在这些组织中，PGC1功能的调节也是至关重要的。我们已经建立了以脂肪组织特异性和可诱导的方式表达NT-PGC1的细胞系和转基因小鼠。在补充性研究中，将从pgc1缺失的小鼠身上永生化棕色脂肪细胞，然后通过稳定转化重新引入NT-pgc1或pGc1，以评估每个剪接变体的独特功能。我们的目标是评估这种新的蛋白质在体内和体外的作用，关于它如何调节PGC1依赖的过程和调节交感神经输入到脂肪和其他代谢活性组织的翻译。

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.