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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK074772-04
Application #
7754892
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Haft, Carol R
Project Start
2007-01-15
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$292,370
Indirect Cost
Name
Lsu Pennington Biomedical Research Center
Department
Type
Organized Research Units
DUNS #
611012324
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
Chang, Ji Suk; Gettys, Thomas W (2013) Analyzing phosphorylation-dependent regulation of subcellular localization and transcriptional activity of transcriptional coactivator NT-PGC-1?. Methods Mol Biol 952:163-73
Jun, Hee-Jin; Gettys, Thomas W; Chang, Ji Suk (2012) Transcriptional Activity of PGC-1? and NT-PGC-1? Is Differentially Regulated by Twist-1 in Brown Fat Metabolism. PPAR Res 2012:320454
Chang, Ji Suk; Fernand, Vivian; Zhang, Yubin et al. (2012) NT-PGC-1? protein is sufficient to link ?3-adrenergic receptor activation to transcriptional and physiological components of adaptive thermogenesis. J Biol Chem 287:9100-11
Chang, Ji Suk; Huypens, Peter; Zhang, Yubin et al. (2010) Regulation of NT-PGC-1alpha subcellular localization and function by protein kinase A-dependent modulation of nuclear export by CRM1. J Biol Chem 285:18039-50
Zhang, Yubin; Huypens, Peter; Adamson, Aaron W et al. (2009) Alternative mRNA splicing produces a novel biologically active short isoform of PGC-1alpha. J Biol Chem 284:32813-26
Morrison, Christopher D; Huypens, Peter; Stewart, Laura K et al. (2009) Implications of crosstalk between leptin and insulin signaling during the development of diet-induced obesity. Biochim Biophys Acta 1792:409-16
Stewart, L K; Wang, Z; Ribnicky, D et al. (2009) Failure of dietary quercetin to alter the temporal progression of insulin resistance among tissues of C57BL/6J mice during the development of diet-induced obesity. Diabetologia 52:514-23
Blumer, Joe B; Lord, Kevin; Saunders, Thomas L et al. (2008) Activator of G protein signaling 3 null mice: I. Unexpected alterations in metabolic and cardiovascular function. Endocrinology 149:3842-9
Stewart, Laura K; Soileau, Jeff L; Ribnicky, David et al. (2008) Quercetin transiently increases energy expenditure but persistently decreases circulating markers of inflammation in C57BL/6J mice fed a high-fat diet. Metabolism 57:S39-46
Morrison, Christopher D; White, Christy L; Wang, Zhong et al. (2007) Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age. Endocrinology 148:433-40

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