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Transcriptional Activity of PGC-1α and NT-PGC-1α Is Differentially Regulated by Twist-1 in Brown Fat Metabolism.

ABSTRACT: Brown fat expresses two PGC-1α isoforms (PGC-1α and NT-PGC-1α) and both play a central role in the regulation of cellular energy metabolism and adaptive thermogenesis by interacting with a wide range of transcription factors including PPARγ, PPARα, ERRα, and NRF1. PGC-1α consists of 797 amino acids, whereas alternative splicing of the PGC-1α gene produces a shorter protein called NT-PGC-1α (aa 1-270). We report in this paper that transcriptional activity of PGC-1α and NT-PGC-1α is differently affected by the transcriptional regulator, Twist-1. Twist-1 suppresses PGC-1α but not NT-PGC-1α. The inhibition of PGC-1α activity by Twist-1 is mediated by direct interaction through the C-terminal region of PGC-1α (aa 353-797). Thus, the absence of the corresponding C-terminal domain in NT-PGC-1α allows NT-PGC-1α to be free from Twist-1-mediated inhibition. Overexpression of Twist-1 in brown adipocytes suppresses transcription of a subset of PGC-1α-target genes involved in mitochondrial fatty acid oxidation and uncoupling (CPT1β, UCP1, and ERRα). In contrast, NT-PGC-1α-mediated induction of these genes is unaffected by Twist-1. These findings show that differences in inhibitory protein-protein interactions of PGC-1α and NT-PGC-1α with Twist-1 lead to differential regulation of their function by Twist-1.

SUBMITTER: Jun HJ

PROVIDER: S-EPMC3474972 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The β3-adrenergic receptor (AR) signaling pathway is a major component of adaptive thermogenesis in brown and white adipose tissue during cold acclimation. The β3-AR signaling highly induces the expression of transcriptional coactivator PGC-1α and its splice variant N-terminal (NT)-PGC-1α, which in turn activate the transcription program of adaptive thermogenesis by co-activating a number of transcription factors. We previously reported that NT-PGC-1α 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-1α-responsive genes in brown adipocytes to identify genes potentially regulated by NT-PGC-1α. Canonical pathway analysis revealed that a number of genes upregulated by NT-PGC-1α are highly enriched in mitochondrial pathways including fatty acid transport and β-oxidation, TCA cycle and electron transport system, thus reinforcing the crucial role of NT-PGC-1α in the enhancement of mitochondrial function. Moreover, canonical pathway analysis of NT-PGC-1α-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-1α-/- mouse that is deficient in full-length PGC-1α (FL-PGC-1α) but expresses a slightly shorter and functionally equivalent form of NT-PGC-1α (NT-PGC-1α254). The β3-AR-induced increase of NT-PGC-1α254 in FL-PGC-1α-/- 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 β3-AR activation resulted in attenuation of adipose tissue expansion in FL-PGC-1α-/- adipose tissue under the high-fat diet condition. Together, the data strengthen our previous findings that NT-PGC-1α regulates mitochondrial genes involved in thermogenesis and oxidative metabolism in brown and white adipocytes and further suggest that NT-PGC-1α regulates a broad spectrum of genes to meet cellular needs for adaptive thermogenesis.

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Transcriptional Activity of PGC-1α and NT-PGC-1α Is Differentially Regulated by Twist-1 in Brown Fat Metabolism.

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