Regulation of Brown and White Adipocyte Transcriptome by the Transcriptional Coactivator NT-PGC-1?.

ABSTRACT: The ?3-adrenergic receptor (AR) signaling pathway is a major component of adaptive thermogenesis in brown and white adipose tissue during cold acclimation. The ?3-AR signaling highly induces the expression of transcriptional coactivator PGC-1? and its splice variant N-terminal (NT)-PGC-1?, which in turn activate the transcription program of adaptive thermogenesis by co-activating a number of transcription factors. We previously reported that NT-PGC-1? is able to increase mitochondrial number and activity in cultured brown adipocytes by promoting the expression of mitochondrial and thermogenic genes. In the present study, we performed genome-wide profiling of NT-PGC-1?-responsive genes in brown adipocytes to identify genes potentially regulated by NT-PGC-1?. Canonical pathway analysis revealed that a number of genes upregulated by NT-PGC-1? are highly enriched in mitochondrial pathways including fatty acid transport and ?-oxidation, TCA cycle and electron transport system, thus reinforcing the crucial role of NT-PGC-1? in the enhancement of mitochondrial function. Moreover, canonical pathway analysis of NT-PGC-1?-responsive genes identified several metabolic pathways including glycolysis and fatty acid synthesis. In order to validate the identified genes in vivo, we utilized the FL-PGC-1?-/- mouse that is deficient in full-length PGC-1? (FL-PGC-1?) but expresses a slightly shorter and functionally equivalent form of NT-PGC-1? (NT-PGC-1?254). The ?3-AR-induced increase of NT-PGC-1?254 in FL-PGC-1?-/- brown and white adipose tissue was closely associated with elevated expression of genes involved in thermogenesis, mitochondrial oxidative metabolism, glycolysis and fatty acid synthesis. Increased adipose tissue thermogenesis by ?3-AR activation resulted in attenuation of adipose tissue expansion in FL-PGC-1?-/- adipose tissue under the high-fat diet condition. Together, the data strengthen our previous findings that NT-PGC-1? regulates mitochondrial genes involved in thermogenesis and oxidative metabolism in brown and white adipocytes and further suggest that NT-PGC-1? regulates a broad spectrum of genes to meet cellular needs for adaptive thermogenesis.

SUBMITTER: Kim J 

PROVIDER: S-EPMC4959749 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature