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Regulation of brown and white adipocyte transcriptome by the transcriptional coactivator NT-PGC-1[alpha]
Ist Teil von
PloS one, 2016-07, Vol.11 (7), p.e0159990
Ort / Verlag
Public Library of Science
Erscheinungsjahr
2016
Link zum Volltext
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
The [beta].sub.3 -adrenergic receptor (AR) signaling pathway is a major component of adaptive thermogenesis in brown and white adipose tissue during cold acclimation. The [beta].sub.3 -AR signaling highly induces the expression of transcriptional coactivator PGC-1[alpha] and its splice variant N-terminal (NT)-PGC-1[alpha], 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[alpha] 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[alpha]-responsive genes in brown adipocytes to identify genes potentially regulated by NT-PGC-1[alpha]. Canonical pathway analysis revealed that a number of genes upregulated by NT-PGC-1[alpha] are highly enriched in mitochondrial pathways including fatty acid transport and [beta]-oxidation, TCA cycle and electron transport system, thus reinforcing the crucial role of NT-PGC-1[alpha] in the enhancement of mitochondrial function. Moreover, canonical pathway analysis of NT-PGC-1[alpha]-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[alpha].sup.-/- mouse that is deficient in full-length PGC-1[alpha] (FL-PGC-1[alpha]) but expresses a slightly shorter and functionally equivalent form of NT-PGC-1[alpha] (NT-PGC-1[alpha].sup.254). The [beta].sub.3 -AR-induced increase of NT-PGC-1[alpha].sup.254 in FL-PGC-1[alpha].sup.-/- 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 [beta].sub.3 -AR activation resulted in attenuation of adipose tissue expansion in FL-PGC-1[alpha].sup.-/- adipose tissue under the high-fat diet condition. Together, the data strengthen our previous findings that NT-PGC-1[alpha] regulates mitochondrial genes involved in thermogenesis and oxidative metabolism in brown and white adipocytes and further suggest that NT-PGC-1[alpha] regulates a broad spectrum of genes to meet cellular needs for adaptive thermogenesis.