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

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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.